Compositions and methods for modulating scap activity

ABSTRACT

Oligonucleotides and compositions including the same are disclosed that modulate (e.g., inhibit, limit or reduce) sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) activity. Methods of making and using the oligonucleotides also are disclosed, particularly uses relating to treating diseases, disorders, and/or conditions associated with SCAP activity such as nonalcoholic fatty liver disease (NAFLD), (NASH), dyslipidemia, atherosclerotic cardiovascular disease (ASCVD), and/or other SCAP-associated conditions, diseases, and/or disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority under 35 U.S.C. § 119(e) fromU.S. Provisional Application No. 63/363,091, filed Apr. 15, 2022, whichis incorporated herein by reference in its entirety.

TECHNICAL FIELD

The disclosure relates generally to biology and medicine, and moreparticularly it relates to oligonucleotides and compositions includingthe same for modulating (e.g., inhibiting or reducing) sterol regulatoryelement-binding protein (SREBP) cleavage-activating protein (SCAP)activity, as well as their use for treating conditions, diseases and/ordisorders associated with SCAP.

BACKGROUND

SCAP is a cholesterol-binding endoplasmic reticulum (ER) membraneprotein encoded by SCAP that binds and transports SREBP transcriptionfactors from the ER to the Golgi apparatus for processing. Onceprocessed in the Golgi apparatus, SREBP transcription factors migrate tothe nucleus where they participate in regulating genes involved in lipidhomeostasis. SREBP1a, SREBP1c and SREBP2 are regulated by the SREBPcleavage-activating protein (SCAP) encoded by the SCAP gene. SREBP1c isthe most abundant SREBP in the liver and its regulation is important formaintaining lipid homeostasis. Specifically, SREBPs affect lipidhomeostasis by modulating genes involved in lipid biosynthesis as wellas modulating genes involved in lipid clearance (e.g., low-densitylipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexintype (PCSK9)). SCAP also plays a role in NLR family pyrin domaincontaining 3 (NLRP3) inflammasome activation.

Human SCAP is ubiquitously expressed throughout the body, but proteinexpression is highest in the bone marrow, brain, endocrine tissue,gastrointestinal tract, liver, lymphoid tissue, muscle tissue, pancreas,reproductive organs, and respiratory tract. The role SCAP plays inregulating the transcription of genes involved in lipid homeostasis makeit a promising therapeutic target to attenuate NASH progression atvarious stages.

Despite the existence of some therapeutics toward SCAP, there is a needfor additional therapeutics for inhibiting or reducing SCAP activity fortreating liver disease, especially NAFLD and non-alcoholicsteatohepatitis (NASH).

BRIEF SUMMARY

To address this need, the disclosure describes compositions for andmethods of treating a disease, disorder and/or condition related to SCAPactivity. The disclosure is based, in part, on discovering anddeveloping double-stranded (ds) oligonucleotides (e.g., RNAioligonucleotides) for selectively modulating (e.g., inhibiting and/orreducing) SCAP activity in, for example, the liver. Accordingly, targetsequences within SCAP are identified, and RNAi oligonucleotides thatbind to these target sequences and inhibit SCAP mRNA expression aregenerated. As shown herein, some oligonucleotides inhibit at least humanand non-human primate (NHP) (i.e., double-common), while others inhibitmouse, human and NHP (i.e., triple-common) SCAP activity in the liver.Without being bound by theory, the RNAi oligonucleotides herein areuseful for treating a disease, disorder and/or condition associated withSCAP activity (e.g., liver diseases such as, for example, NAFLD, NASH,dyslipidemia, and/or atherosclerotic cardiovascular disease (ASCVD)).

Accordingly, the disclosure describes RNAi oligonucleotides for reducingor inhibiting SCAP activity that include a sense strand (also known as apassenger strand) and/or an antisense strand (also known as a guidestrand), where the sense strand has a sequence as set forth in Table 3,and where the antisense strand has a sequence as set forth in Table 3.

In some embodiments, the sense strand has a sequence as set forth inTable 3 (e.g., any one of the odd numbers of SEQ ID NOs: 9 to 392),especially any one of SEQ ID NOs: 139, 147, 221, 273, 321, 333, and 361.

In some embodiments, the antisense strand has a sequence as set forth inTable 3 (e.g., any one of the even numbers of SEQ ID NOs: 9 to 392),especially any one of SEQ ID NOs: 140, 148, 222, 274, 322, 334, and 362.

Alternatively, the disclosure describes RNAi oligonucleotides forreducing or inhibiting SCAP activity that include a sense strand and/oran antisense strand, where the sense strand has a sequence as set forthin Table 4, and where the antisense strand has a sequence as set forthin Table 4.

In some embodiments, the sense strand has a sequence as set forth inTable 4 (e.g., any one of the odd numbers of SEQ ID NOs: 393 to 776),especially any one of SEQ ID NOs: 523, 531, 605, 657, 705, 717, and 745.

In some embodiments, the antisense strand has a sequence as set forth inTable 4 (e.g., any one of the even numbers of SEQ ID NOs: 393 to 776),especially any one of SEQ ID NOs: 524, 532, 606, 658, 706, 718, and 746.

Alternatively, RNAi oligonucleotides are described for reducing orinhibiting SCAP activity that include a sense strand and an antisensestrand, where the sense and antisense strands form a duplex region, andwhere the antisense strand has a region of complementarity to a SCAPmRNA target sequence of any one of SEQ ID NOs: 777 to 783.

In any of the embodiments above, the sense strand is from about 15nucleotides to about 50 nucleotides in length. In some embodiments, thesense strand is from about 20 nucleotides to about 40 nucleotides inlength. In some embodiments, the sense strand is 36 nucleotides inlength.

In any of the embodiments above, the antisense strand is from about 15nucleotides to about 30 nucleotides in length. In some embodiments, theantisense strand is from about 20 nucleotides to about 25 nucleotides.In some embodiments, the antisense strand is 22 nucleotides in length.

In any of the embodiments above, the duplex region is from about 19nucleotides in length to about 21 nucleotides in length. In certainembodiment, the duplex region is 20 nucleotides in length.

In any of the embodiments above, the region of complementarity is atleast 15 contiguous nucleotides in length. In some embodiments, theregion of complementarity is from about 19 contiguous nucleotides inlength to about 21 contiguous nucleotides in length. In otherembodiments, the region of complementarity is 19 contiguous nucleotidesin length or 21 contiguous nucleotides in length.

In any of the embodiments above, the RNAi oligonucleotides include onthe sense strand a 3′ end a stem-loop set forth as: S1-L-S2, where afirst stem portion (S1) is complementary to a second stem portion (S2),and where L is a loop between S1 and S2 of about 3 to about 5nucleotides in length.

In any of the embodiments above, the antisense strand, the sense strand,or both have an overhang sequence. In some embodiments, the antisensestrand includes a 3′ overhang of 1 or more nucleotides in length. Inother embodiments, the 3′ overhang sequence is 2 nucleotides in lengthsuch as, for example, GG.

Oligonucleotides also are described that include an antisense strand anda sense strand for reducing or inhibiting SCAP activity, where theantisense strand can be from about 21 nucleotides to about 27nucleotides in length and has a region of complementarity to SCAP mRNA,wherein the sense strand includes a stem-loop at its 3′ end set forthas: S1-L-S2, wherein S1 is complementary to S2, wherein L forms a loopbetween S1 and S2 from about 3 nucleotides to about 5 nucleotides inlength, and wherein the antisense strand and the sense strand form aduplex structure of at least about 19 nucleotides in length but are notcovalently linked.

In some embodiments, the loop L is a triloop (triL) or a tetraloop(tetraL). In some embodiments, L is a tetraL of 4 nucleotides in length.In certain embodiments, L is a tetraL having a sequence of 5′-GAAA-3′.

In some embodiments, S1 and S2 are 1-10 nucleotides in length and havethe same length. In other embodiments, S1 and S2 are 1 nucleotide, 2nucleotides, 3 nucleotides, 4 nucleotides, 5 nucleotides, 6 nucleotides,7 nucleotides, 8 nucleotides, 9 nucleotides, or 10 nucleotides inlength. In other embodiments, S1 and S2 are 6 nucleotides in length. Incertain embodiments, the stem-loop comprises the sequence5′-GCAGCCGAAAGGCUGC-3′ (SEQ ID NO: 784).

In some embodiments, the sense strand is 25 nucleotides in length andthe antisense strand is 27 nucleotides in length. In other embodiments,the sense strand is 36 nucleotides in length and the antisense strand is22 nucleotides in length.

In the embodiments above, the duplex region includes a 3′ overhangsequence on the antisense strand. In some embodiments, the 3′ overhangsequence on the antisense strand is 2 nucleotides in length.

In any of the embodiments above, at least one nucleotide in anoligonucleotide is a modified nucleotide. In some embodiments, allnucleotides in the oligonucleotide are modified except for nucleotidesin the stem-loop (i.e., S1-L-S2). In other embodiments, all nucleotidesin the oligonucleotide are modified except for nucleotides in the L.

In some embodiments, the modified nucleotide includes a 2′-modificationsuch as, for example, 2′-aminoethyl (EA), 2′-fluoro (2′-F), 2′-O-methyl(2′-OMe), 2′-O-methoxyethyl (2′-MOE) and2′-deoxy-2′-fluoro-β-arabinonucleic acid (2′-FANA). In certainembodiments, all nucleotides in an oligonucleotide include a2′-modification such as, for example, 2′-F or 2′-OMe. In someembodiments, about 18% to about 23%, or 18%, 19%, 20%, 21%, 22%, or 23%of the nucleotides of the sense strand comprise a 2′-F modification. Inother embodiments, about 38% to about 43%, or 38%, 39%, 40%, 41%, 42%,or 43% of the nucleotides of the sense strand comprise a 2′-Fmodification. In some embodiments, about 25% to about 35%, or 25%, 26%,27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35% of the nucleotides of theantisense strand comprise a 2′-F modification. In some embodiments,about 25% to about 35%, or 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%,34%, or 35% of the nucleotides of the oligonucleotide comprise a 2′-Fmodification. In some embodiments, about 35% to about 45%, or 35%, 36%,37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, or 45% of the nucleotides of theoligonucleotide comprise a 2′-F modification.

In any of the embodiments above, at least one nucleotide in anoligonucleotide includes a modified internucleotide linkage. In someembodiments, the modified internucleotide linkage is a phosphorothioate(PS) linkage.

In any of the embodiments above, a 4′-carbon of a sugar of a5′-nucleotide of the antisense strand includes a phosphate analog suchas, for example, an oxymethylphosphonate, vinylphosphonate ormalonylphosphonate. Alternatively, or optionally, the phosphate analogis a 4′-phosphate analog including 5′-methoxyphosphonate-4′-oxy.

In any of the embodiments above, at least one nucleotide of anoligonucleotide is conjugated to one or more targeting ligands such as,for example, an amino sugar, carbohydrate, cholesterol, lipid, orpolypeptide. In some embodiments, the targeting ligand is aN-acetylgalactosamine (GalNAc) moiety. In other embodiments, the GalNAcmoiety is a monovalent GalNAc moiety, a bivalent GalNAc moiety, atrivalent GalNAc moiety, or a tetravalent GalNAc moiety.

In some embodiments, the targeting ligands are conjugated to one or morenucleotides of L of the stem loop. In certain embodiments, up to 4nucleotides of L of the stem-loop are each conjugated to a monovalentGalNAc moiety.

In certain embodiments, one or more nucleotides at positions 8, 9, 10,or 11 of the sense strand are modified with a 2′-F. In otherembodiments, the sugar moiety at each nucleotide at positions 1 to 7, 12to 27 and 31 to 36 in the sense strand is modified with a 2′-OMe. Incertain embodiments, nucleotides at positions 8 to 11 of the sensestrand are modified with a 2′-F, and positions 1 to 7, 12 to 27 and 31to 36 are modified with a 2′-OMe.

In certain other embodiments, one or more nucleotides at positions 2 to5, 7, 10 and 14 of the antisense strand are modified with 2′-F, and oneor more nucleotides at positions 1, 6, 8-9, 11-13 and 15-22 modifiedwith a 2′-OMe. In other embodiments, the antisense strand includes a2′-F-modified nucleotide at positions 2 to 5, 7, 10 and 14, and a2′-OMe-modified nucleotide at positions 1, 6, 8 to 9, 11 to 13 and 15 to22.

In certain embodiments, the oligonucleotides have a modification patternas shown in FIG. 1 .

In any of the embodiments above, the oligonucleotide is a RNAioligonucleotide. In some embodiments, the RNAi oligonucleotide includesa sense strand having a nucleotide sequence as set forth in Table 3,especially any one of SEQ ID NOs: 139, 147, 221, 273, 321, 333, and 361.In certain embodiments, the RNAi oligonucleotide includes a sense strandhaving a nucleotide sequence as set forth in Table 4, especially any oneof SEQ ID NOs: 523, 531, 605, 657, 705, 717, and 745. In someembodiments, the RNAi oligonucleotide includes an antisense strandhaving a nucleotide sequence as set for the in Table 3, especially anyone of SEQ ID NOs: 140, 148, 222, 274, 322, 334, and 362. In certainembodiments, the RNAi oligonucleotide includes an antisense strandhaving a nucleotide sequence as set forth in Table 4, especially any oneof SEQ ID NOs: 524, 532, 606, 658, 706, 718, and 746.

In certain embodiments, the RNAi oligonucleotide includes a sense strandhaving a nucleotide sequence of any one of SEQ ID NOs: 139, 147, 221,273, 321, 333, and 361, and an antisense strand having a nucleotidesequence of any one of SEQ ID NOs: 140, 148, 222, 274, 322, 334, and362.

In certain other embodiments, the sense strand and the antisense strandof the RNAi oligonucleotide, respectively, are selected from:

-   -   (a) SEQ ID NOs: 139 and 140,    -   (b) SEQ ID NOs: 147 and 148,    -   (c) SEQ ID NOs: 221 and 222,    -   (d) SEQ ID NOs: 273 and 274,    -   (e) SEQ ID NOs: 321 and 322,    -   (f) SEQ ID NOs: 333 and 334, and    -   (g) SEQ ID NOs: 361 and 362.

In certain embodiments, the RNAi oligonucleotide includes a sense strandhaving a nucleotide sequence of any one of SEQ ID NOs: 147 and 333, andan antisense strand having a nucleotide sequence of any one of SEQ IDNOs: 148 and 334 respectively.

In certain embodiments, the RNAi oligonucleotide includes a sense strandhaving a nucleotide sequence of any one of SEQ ID NOs: 523, 531, 605,657, 705, 717, and 745, and an antisense strand having a nucleotidesequence of any one of SEQ ID NOs: 524, 532, 606, 658, 706, 718, and 746respectively.

In certain other embodiments, the sense strand and the antisense strandof the RNAi oligonucleotide, respectively, are selected from:

-   -   (a′) SEQ ID NOs: 523 and 524,    -   (b′) SEQ ID NOs: 531 and 532,    -   (c′) SEQ ID NOs: 605 and 606,    -   (d′) SEQ ID NOs: 657 and 658,    -   (e′) SEQ ID NOs: 705 and 706,    -   (f′) SEQ ID NOs: 717 and 718, and    -   (g′) SEQ ID NOs: 745 and 746.

In certain embodiments, the RNAi oligonucleotide includes a sense strandhaving a nucleotide sequence of any one of SEQ ID NOs: 531 and 717, andan antisense strand having a nucleotide sequence of any one of SEQ IDNOs: 532 and 718 respectively.

RNAi oligonucleotides also are described for inhibiting or reducing SCAPactivity that include a sense strand and an antisense strand, where thesense strand and the antisense strand form a duplex region, where allnucleotides of the sense strand and the antisense strand include amodification of a base, a sugar and/or an internucleotide linkage, wherethe antisense strand includes a region of complementarity to a SCAP mRNAtarget sequence of one of SEQ ID NOs: 777 to 783, and where the regionof complementarity is at least about 15 contiguous nucleotides inlength.

In other aspects, pharmaceutical compositions are described that includeat least one oligonucleotide herein, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier, delivery agentor excipient. In some embodiments, the pharmaceutical compositionsinclude an additional therapeutic agent such as, for example, alipid-lowering agent, an antidiabetic agent, or anti-obesity agent.

In other aspects, methods are described for reducing SCAP activity in acell, a population of cells, a tissue, an organ, or an individual thatinclude at least a step of administering/contacting the cell, thepopulation of cells, the tissue, the organ, or the individual with anoligonucleotide herein or a pharmaceutical composition herein. In someembodiments, reducing SCAP activity includes reducing an amount or levelof SCAP mRNA, an amount or level of SCAP protein, SCAP activity or acombination thereof in the cell, the population of cells, the tissue,the organ, or the individual. In some embodiments, the cell, the cellpopulation, the tissue, the organ, or the individual has a disease,disorder, or condition associated with SCAP activity. In certainembodiments, the disease, disorder, or condition associated with SCAPactivity is NAFLD, NASH, dyslipidemia, and/or ASCVD.

In other aspects, methods are described for treating an individualhaving or suspected of having a disease, disorder, or conditionassociated with SCAP activity. The methods include at least a step ofadministering to an individual in need thereof an effective amount of anoligonucleotide herein or a pharmaceutical composition herein. In someembodiments, the disease, disorder, or condition associated with SCAPactivity is NAFLD, NASH, dyslipidemia, and/or ASCVD. In someembodiments, the oligonucleotide or pharmaceutical composition isadministered daily, weekly, monthly, quarterly, yearly via subcutaneous(SQ) administration, especially monthly or quarterly.

In some embodiments, the individual has alcoholic hepatitis (AH),alcoholic liver disease (ALD), cholangiocarcinoma (CCA), cirrhosis,hepatic fibrosis, hepatic inflammation, hepatocellular carcinoma (HCC),liver steatosis, NAFLD, NASH, primary sclerosing cholangitis (PSC),hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, diabetes,and/or obesity, and/or ASCVD.

In any of the embodiments above, the methods may comprise additionalsteps such as measuring or obtaining genotype information, SCAP mRNA,SCAP protein levels, SCAP activity, the individual's weight and/or bloodglucose and/or cholesterol and/or TG, and then comparing such obtainedvalues to one or more baseline values or previously obtained values toassess the effectiveness of contacting or administering.

In any of the embodiments above, the methods include administering theRNAi oligonucleotide or pharmaceutical composition simultaneously,separately, or sequentially with a second composition or a secondtherapeutic agent. In some embodiments, the second composition or asecond therapeutic agent is a SCAP antibody or fragment thereof, alipid-lowering agent, an anti-diabetic agent or anti-obesity agent. Insome embodiments, the second composition or second therapeutic agent isadministered with a frequency same as the RNAi oligonucleotide (i.e.,every other day, twice a week, or even weekly). In other embodiments,the second composition or second therapeutic agent is administered witha frequency distinct from the RNAi oligonucleotide. Likewise, in otherembodiments, the second composition or second therapeutic agent isadministered via the same route as the RNAi oligonucleotide (e.g., SQ).In still other embodiments, the second composition or second therapeuticagent is administered via a route that differs from the RNAioligonucleotide).

In other aspects, uses are described for the RNAi oligonucleotidesherein for treating a disease, disorder, or condition associated withSCAP activity, which optionally are administered simultaneously,separately, or sequentially (i.e., in combination) with a secondcomposition or second therapeutic agent.

In other aspects, uses are described for the RNAi oligonucleotidesherein in manufacturing a medicament for treating a disease, disorder,or condition associated with SCAP activity, where the medicamentoptionally further includes a second composition or second therapeuticagent.

In other aspects, kits are described that include at least oneoligonucleotide herein, an optional pharmaceutically acceptable carrier,and a package insert having instructions for administering the same toan individual having a disease, disorder, or condition associated withSCAP activity.

An advantage of the oligonucleotides and compositions herein is thatsuppressed SCAP activity exerts a beneficial effect on the entirespectrum of NAFLD, NASH, dyslipidemia and/or ASCVD.

BRIEF DESCRIPTION OF THE DRAWINGS

The advantages, effects, features, and objects other than those setforth above will become more readily apparent when consideration isgiven to the detailed description below. Such detailed descriptionrefers to the following drawing(s), where:

FIG. 1 discloses a schematic depicting the structure and chemicalmodification pattern for a generic GalNAc-conjugated SCAPoligonucleotides (modification pattern M1).

DETAILED DESCRIPTION

Overview

NAFLD and NASH are serious public health burdens as they are chronicliver disorders that begin with hepatic TG accumulation (steatosis) andprogress to hepatic inflammation and fibrosis, cirrhosis and even livercancer. SCAP is a transcription regulator that has been shown to beassociated with NAFLD and NASH. Here, targeted silencing of SCAP mRNAvia RNAi can prevent processing of active SREBP and downstreamtranscriptional changes in regulating de novo lipogenesis and TGaccumulation within the liver.

RNAi is a process of introducing exogeneous RNA into a cell leading tospecific degradation of the mRNA encoding the targeted protein with aresultant decrease in target gene expression.

In humans, SCAP is 1279 amino acids in length with a predicted molecularweight of 140 kD. Exemplary nucleic acid sequences for SCAP can be foundin NCBI Ref. Seq. No. NM_012235 (isoform 1) and NM_001320044 (isoform 2)(human); NM_001001144 and NM_001103162 (mouse); NM_001100966 (rat); andXM_001100342 (primate). Other exemplary nucleic acid sequences for SCAPinclude NCBI Ref. Seqs Nos. XM_017005918 (human variant X1),XM_011533501 (human variant X2), XM_005264967 (human variant X3),XM_005264968 (human variant X4), XM_011533502 (human variant X5),XM_005264971 (human variant X6), XM_017005921 (human variant X7),XM_006512083 (mouse variant X1), XM_006512084 (mouse variant X2),XM_006512085 (mouse variant X3), XM_006243922 (rat variant X1),XM_017595596 (rat variant X2), XM_006243923 (rat variant X3),XM_006243924 (rat variant X5), XM_006243925 (rat variant X5),XM_017595597 (rat variant X6), XM_005546961 (primate variant X1),XM_015445807 (primate variant X2), XM_005546962 (primate variant X3),XM_005546963 (primate variant X4), and XM_015445808 (primate variantX5). One of skill in the art, however, understands that additionalexamples of SCAP mRNA sequences are readily available using publiclyavailable databases such as, for example, GenBank and UniProt.

Abbreviations and Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of skill in the artto which the disclosure pertains. Although any methods and materialssimilar to or equivalent to those described herein can be used in thepractice or testing of the RNAi oligonucleotides herein, pharmaceuticalcompositions including the same and methods of making and using suchRNAi oligonucleotides, the preferred methods and materials are describedherein.

Moreover, reference to an element by the indefinite article “a” or “an”does not exclude the possibility that more than one element is present,unless the context clearly requires that there be one and only oneelement. The indefinite article “a” or “an” thus usually means “at leastone.”

Furthermore, use of “including,” as well as other forms, such as“include,” “includes” and “included” is not limiting.

Certain definitions used herein are defined as follows:

As used herein, “about” means within a statistically meaningful range ofa value or values such as, for example, a stated concentration, length,molecular weight, pH, sequence similarity, time frame, temperature,volume, etc. Such a value or range can be within an order of magnitudetypically within 20%, more typically within 10%, and even more typicallywithin 5% of a given value or range. The allowable variation encompassedby “about” will depend upon the particular system under study, and canbe readily appreciated by one of skill in the art.

As used herein, “administer,” “administering,” “administration” and thelike refers to providing a substance (e.g., an oligonucleotide herein ora composition herein) to an individual in a manner that ispharmacologically useful (e.g., to treat a disease, disorder, orcondition in the individual).

As used herein, “antisense strand” means an oligonucleotide herein thatis complimentary to a region of a target sequence. Likewise, and as usedherein, “sense strand” means an oligonucleotide herein that iscomplimentary to a region of an antisense strand.

As used herein, “asialoglycoprotein receptor” or “ASGPR” means abipartite C-type lectin formed by a major 48 kDa subunit (ASGPR-1) andminor 40 kDa subunit (ASGPR-2). ASGPR is primarily expressed on thesinusoidal surface of hepatocyte cells and has a major role in binding,internalizing and subsequent clearing of circulating glycoproteins thatcontain terminal galactose or GalNAc residues (asialoglycoproteins).

As used herein, “attenuate,” “attenuating,” “attenuation” and the likerefers to reducing or effectively halting. As a non-limiting example,one or more of the treatments herein may reduce or effectively halt theonset or progression of AH, ALD, CCA, cirrhosis, hepatic fibrosis,hepatic inflammation, HCC, liver steatosis, NAFLD, NASH and PSC, as wellas related diseases, disorders, and conditions in an individual such as,for example, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia,ASCVD, diabetes and/or obesity. This attenuation may be exemplified by,for example, a decrease in one or more aspects (e.g., symptoms, tissuecharacteristics, and cellular, inflammatory, or immunological activity,etc.) of AH, ALD, CCA, cirrhosis, hepatic fibrosis, hepaticinflammation, HCC, liver steatosis, NAFLD, NASH and PSC, as well asrelated diseases, disorders, and conditions in an individual such as,for example, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia,ASCVD, diabetes and/or obesity; no detectable progression (worsening) ofone or more aspects of AH, ALD, CCA, cirrhosis, hepatic fibrosis,hepatic inflammation, HCC, liver steatosis, NAFLD, NASH and PSC, as wellas related diseases, disorders, and conditions in an individual such as,for example hypercholesterolemia, hyperlipidemia, hypertriglyceridemia,ASCVD, diabetes and/or obesity; or no detectable aspects of AH, ALD,CCA, cirrhosis, hepatic fibrosis, hepatic inflammation, HCC, liversteatosis, NAFLD, NASH and PSC, as well as related diseases, disorders,and conditions in an individual such as, for example,hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, ASCVD,diabetes and/or obesity in an individual when they might otherwise beexpected.

As used herein, “complementary” means a structural relationship betweentwo nucleotides (e.g., on two opposing nucleic acids or on opposingregions of a single nucleic acid strand) that permits the twonucleotides to form base pairs with one another. For example, a purinenucleotide of one nucleic acid that is complementary to a pyrimidinenucleotide of an opposing nucleic acid may base pair together by forminghydrogen bonds with one another. Complementary nucleotides can base pairin the Watson-Crick manner or in any other manner that allows for theformation of stable duplexes. Likewise, two nucleic acids may haveregions of multiple nucleotides that are complementary with each otherto form regions of complementarity, as described herein.

As used herein, “contact,” “contacting” and the like means directly orindirectly introducing or delivering an oligonucleotide such as a RNAioligonucleotide into, for example, a cell by facilitating or effectinguptake or absorption into the cell.

As used herein, “deoxyribonucleotide” means a nucleotide having ahydrogen in place of a hydroxyl at the 2′ position of its pentose sugarwhen compared with a ribonucleotide. A modified deoxyribonucleotide hasone or more modifications or substitutions of atoms other than at the 2′position, including modifications or substitutions in or of thenucleobase, sugar, or phosphate group.

As used herein, “double-stranded oligonucleotide” or “dsoligonucleotide” means an oligonucleotide that is substantially in aduplex form. The complementary base-pairing of duplex region(s) of a dsoligonucleotide can be formed between antiparallel sequences ofnucleotides of covalently separate nucleic acid strands. Likewise,complementary base-pairing of duplex region(s) of a ds oligonucleotidecan be formed between antiparallel sequences of nucleotides of nucleicacid strands that are covalently linked. Moreover, complementarybase-pairing of duplex region(s) of a ds oligonucleotide can be formedfrom single nucleic acid strand that is folded (e.g., via a hairpin) toprovide complementary antiparallel sequences of nucleotides that basepair together. A ds oligonucleotide can include two covalently separatenucleic acid strands that are fully duplexed with one another. However,a ds oligonucleotide can include two covalently separate nucleic acidstrands that are partially duplexed (e.g., having overhangs at one orboth ends). A ds oligonucleotide can include an antiparallel sequence ofnucleotides that are partially complementary, and thus, may have one ormore mismatches, which may include internal mismatches or endmismatches.

As used herein, “duplex,” in reference to nucleic acids (e.g.,oligonucleotides), means a structure formed through complementary basepairing of two antiparallel sequences of nucleotides.

As used herein, “excipient” means a non-therapeutic agent that may beincluded in a composition herein, for example, to provide or contributeto a desired consistency or stabilizing effect.

As used herein, “hepatocyte” or “hepatocytes” means cells of theparenchymal tissues of the liver. These cells make up about 70%-85% ofthe liver's mass and manufacture serum albumin, fibrinogen (FBN) and theprothrombin group of clotting factors (except for Factors 3 and 4).Markers for hepatocyte lineage cells include, but are not limited to,transthyretin (Ttr), glutamine synthetase (Glu1), hepatocyte nuclearfactor 1a (Hnf1a) and hepatocyte nuclear factor 4a (Hnf4a). Markers formature hepatocytes may include, but are not limited to, cytochrome P450(Cyp3a11), fumarylacetoacetate hydrolase (Fah), glucose 6-phosphate(G6p), albumin (Alb) and OC2-2F8. See, e.g., Huch et al. (2013) Nature494:247-250.

As used herein, a “hepatotoxic agent” means a chemical compound, virusor other substance that is itself toxic to the liver or can be processedto form a metabolite that is toxic to the liver. Hepatotoxic agents mayinclude, but are not limited to, carbon tetrachloride (CCl₄),acetaminophen (paracetamol), vinyl chloride, arsenic, chloroform, andnonsteroidal anti-inflammatory drugs (such as aspirin andphenylbutazone).

As used herein, “individual” means any mammal, including cats, dogs,mice, rats, and primates, especially humans. Moreover, “subject” or“patient” may be used interchangeably with “individual.”

As used herein, “labile linker” means a linker that can be cleaved(e.g., by acidic pH). Likewise, “fairly stable linker” means a linkerthat cannot be cleaved.

As used herein, “liver inflammation” or “hepatitis” means a physicalcondition in which the liver becomes swollen, dysfunctional and/orpainful, especially because of injury or infection, as may be caused byexposure to a hepatotoxic agent. Symptoms may include jaundice, fatigue,weakness, nausea, vomiting, appetite reduction, and weight loss. Liverinflammation, if left untreated, may progress to fibrosis, cirrhosis,liver failure or liver cancer.

As used herein, “liver fibrosis,” “hepatic fibrosis” or “fibrosis of theliver” refers to an excessive accumulation in the liver of extracellularmatrix proteins, which could include collagens (I, III, and IV), FBN,undulin, elastin, laminin, hyaluronan, and proteoglycans resulting frominflammation and liver cell death. Liver fibrosis, if left untreated,may progress to cirrhosis, liver failure, or liver cancer.

As used herein, “loop” means an unpaired region of a nucleic acid (e.g.,oligonucleotide) that is flanked by two antiparallel regions of thenucleic acid that are sufficiently complementary to one another, suchthat under appropriate hybridization conditions (e.g., in a phosphatebuffer, in a cells), the two antiparallel regions, which flank theunpaired region, hybridize to form a duplex (referred to as a “stem”).

As used herein, “modified internucleotide linkage” means aninternucleotide linkage having one or more chemical modifications whencompared with a reference internucleotide linkage having aphosphodiester bond. A modified nucleotide can be a non-naturallyoccurring linkage. Typically, a modified internucleotide linkage confersone or more desirable properties to a nucleic acid in which the modifiedinternucleotide linkage is present. For example, a modified nucleotidemay improve thermal stability, resistance to degradation, nucleaseresistance, solubility, bioavailability, bioactivity, reducedimmunogenicity, etc.

As used herein, “modified nucleotide” refers to a nucleotide having oneor more chemical modifications when compared with a correspondingreference nucleotide selected from: adenine ribonucleotide, guanineribonucleotide, cytosine ribonucleotide, uracil ribonucleotide, adeninedeoxyribonucleotide, guanine deoxyribonucleotide, cytosinedeoxyribonucleotide and thymidine deoxyribonucleotide. A modifiednucleotide can be a non-naturally occurring nucleotide. A modifiednucleotide can have, for example, one or more chemical modifications inits sugar, nucleobase and/or phosphate group. Additionally oralternatively, a modified nucleotide can have one or more chemicalmoieties conjugated to a corresponding reference nucleotide. Typically,a modified nucleotide confers one or more desirable properties to anucleic acid in which the modified nucleotide is present. For example, amodified nucleotide may improve thermal stability, resistance todegradation, nuclease resistance, solubility, bioavailability,bioactivity, reduced immunogenicity, etc.

As used herein, “nicked tetraloop structure” mean a structure of a RNAioligonucleotide that is characterized by separate sense and antisensestrands, in which the sense strand has a region of complementarity withthe antisense strand, and in which at least one of the strands,generally the sense strand, has a tetraloop configured to stabilize anadjacent stem region formed within the at least one strand.

As used herein, “nucleoside” means a nucleobase-sugar combination, wherethe nucleobase portion is normally a heterocyclic base. The two mostcommon classes of such heterocyclic bases are purines and pyrimidines.The sugar is normally a pentose sugar such as a ribose or a deoxyribose(e.g., 2′-deoxyribose).

As used herein, “nucleotide” means an organic molecule having anucleoside (a nucleobase such as, for example, adenine, cytosine,guanine, thymine, or uracil; and a pentose sugar such as, e.g., riboseor 2′-deoxyribose) and a phosphate group, which can serve as a monomericunit of nucleic acid polymers such as deoxyribonucleic acid (DNA) andribonucleic acid (RNA).

As used herein, “oligonucleotide” means a short nucleic acid molecule(e.g., less than about 100 nucleotides in length). An oligonucleotidemay be single-stranded (ss) or ds. An oligonucleotide may or may nothave duplex regions. As a set of non-limiting examples, anoligonucleotide may be, but is not limited to, a small interfering RNA(siRNA), microRNA (miRNA), short hairpin RNA (shRNA), Dicer substrateinterfering RNA (DsiRNA), antisense oligonucleotide (ASO), short siRNAor ss siRNA. Typically, a ds oligonucleotide is a RNAi oligonucleotide.

As used herein, “overhang” means a terminal non-base pairingnucleotide(s) resulting from one strand or region extending beyond theterminus of a complementary strand with which the one strand or regionforms a duplex. An overhang may include one or more unpaired nucleotidesextending from a duplex region at the 5′ terminus or 3′ terminus of a dsoligonucleotide. The overhang can be a 3′ or 5′ overhang on theantisense strand or sense strand of a ds oligonucleotide.

As used herein, “phosphate analog” means a chemical moiety that mimicsthe electrostatic and/or steric properties of a phosphate group. In someembodiments, a phosphate analog is positioned at the 5′ terminalnucleotide of an oligonucleotide in place of a 5′-phosphate, which isoften susceptible to enzymatic removal. A 5′ phosphate analog caninclude a phosphatase-resistant linkage. Examples of phosphate analogsinclude, but are not limited to, 5′ phosphonates, such as 5′methylenephosphonate (5′-MP) and 5′-(E)-vinylphosphonate (5′-VP). Anoligonucleotide can have a phosphate analog at a 4′-carbon position ofthe sugar (referred to as a “4′-phosphate analog”) at a 5′-terminalnucleotide. An example of a 4′-phosphate analog is oxymethylphosphonate,in which the oxygen atom of the oxymethyl group is bound to the sugarmoiety (e.g., at its 4′-carbon) or analog thereof. See, e.g., Intl.Patent Application Publication No. WO 2018/045317. Other modificationshave been developed for the 5′ end of oligonucleotides (see, e.g., Intl.Patent Application No. WO 2011/133871; U.S. Pat. No. 8,927,513; andPrakash et al. (2015) Nucleic Acids Res. 43:2993-3011).

As used herein, or “SCAP-associated condition,” “SCAP-associateddisease” or “SCAP-associated disorder” means such a disease, disorder,or condition having increased SCAP activity and/or the presence of, forexample, a SCAP polymorphism. Exemplary SCAP-associated conditions,diseases or disorders include, but are not limited to, AH, ALD, CCA,cirrhosis, hepatic fibrosis, hepatic inflammation, HCC, liver steatosis,NAFLD, NASH and PSC, as well as related diseases, disorders, andconditions in an individual such as, for example hypercholesterolemia,hyperlipidemia, hypertriglyceridemia, ASCVD, diabetes and/or obesity.

As used herein, “reduced expression” or “reduced activity,” and withrespect to a gene (e.g., SCAP), means a decrease in the amount or levelof RNA transcript (e.g., SCAP mRNA) or protein (e.g., SCAP protein)encoded by the gene and/or a decrease in the amount or level of activityof the gene or protein in a cell, a population of cells, a sample or asubject, when compared to an appropriate reference (e.g., a referencecell, population of cells, sample or individual). For example, the actof contacting a cell with an oligonucleotide herein (e.g., anoligonucleotide having an antisense strand having a nucleotide sequencethat is complementary to a nucleotide sequence including SCAP mRNA) mayresult in a decrease in the amount or level of mRNA, protein and/oractivity (e.g., via degradation of SCAP mRNA by the RNAi pathway) whencompared to a cell that is not treated with the ds oligonucleotide.Similarly, and as used herein, “reducing expression” or “reducingactivity” means an act that results in reduced expression of a gene(e.g., SCAP). Specifically, and as used herein, “reduction of SCAPexpression” or “reduction of SCAP activity” means a decrease in theamount or level of SCAP activity such as, for example, SCAP mRNA and/orSCAP protein and/or SCAP activity in a cell, a population of cells, asample or a subject when compared to an appropriate reference (e.g., areference cell, population of cells, tissue or individual).

As used herein, “region of complementarity” means a sequence ofnucleotides of a nucleic acid (e.g., a ds oligonucleotide) that issufficiently complementary to an antiparallel sequence of nucleotides topermit hybridization between the two sequences of nucleotides underappropriate hybridization conditions (e.g., in a phosphate buffer, in acell, etc.). An oligonucleotide herein includes a targeting sequencehaving a region of complementary to a mRNA target sequence.

As used herein, “ribonucleotide” means a nucleotide having a ribose asits pentose sugar, which contains a hydroxyl group at its 2′ position. Amodified ribonucleotide is a ribonucleotide having one or moremodifications or substitutions of atoms other than at the 2′ position,including modifications or substitutions in or of the nucleobase, sugar,or phosphate group.

As used herein, “iRNA,” “iRNA agent,” “RNAi,” “RNAi agent” and “RNAinterference agent” means an agent such as, for example, a RNAioligonucleotide, which contains RNA and which mediates the targetedcleavage of an RNA transcript via a RNA-induced silencing complex (RISC)pathway to direct sequence-specific degradation of mRNA via RNAinterference. The agent thus modulates, inhibits or reduces geneexpression in a cell.

As used herein, “RNAi oligonucleotide” refers to either (a) a dsoligonucleotide having a sense strand and antisense strand, in which theantisense strand or part of the antisense strand is used by theArgonaute 2 (Ago2) endonuclease in the cleavage of a target mRNA or (b)a ss oligonucleotide having a single antisense strand, where thatantisense strand (or part of that antisense strand) is used by the Ago2endonuclease in the cleavage of a target mRNA.

As used herein, “strand” refers to a single, contiguous sequence ofnucleotides linked together through internucleotide linkages (e.g.,phosphodiester linkages or phosphorothioate linkages). A strand can havetwo free ends (e.g., a 5′ end and a 3′ end).

As used herein, “synthetic” refers to a nucleic acid or other moleculethat is artificially synthesized (e.g., using a machine such as, forexample, a solid-state nucleic acid synthesizer) or that is otherwisenot derived from a natural source (e.g., a cell or organism) thatnormally produces the nucleic acid or other molecule.

As used herein, “targeting ligand” means a molecule (e.g., an aminosugar, carbohydrate, cholesterol, lipid, or polypeptide) thatselectively binds to a cognate molecule (e.g., a receptor) of a tissueor cell of interest and that is conjugatable to another substance fortargeting another substance to the tissue or cell of interest. Forexample, a targeting ligand may be conjugated to an oligonucleotideherein for purposes of targeting the oligonucleotide to a specifictissue or cell of interest. A targeting ligand can selectively bind to acell surface receptor. Accordingly, a targeting ligand, when conjugatedto an oligonucleotide, facilitates delivery of the oligonucleotide intoa particular cell through selective binding to a receptor expressed onthe surface of the cell and endosomal internalization by the cell of thecomplex comprising the oligonucleotide, targeting ligand and receptor.Moreover, a targeting ligand can be conjugated to an oligonucleotide viaa linker that is cleaved following or during cellular internalizationsuch that the oligonucleotide is released from the targeting ligand inthe cell.

As used herein, “tetraloop” or “teraL” means a loop that increasesstability of an adjacent duplex formed by hybridization of flankingsequences of nucleotides. The increase in stability is detectable as anincrease in melting temperature (T_(m)) of an adjacent stem duplex thatis higher than the T_(m) of the adjacent stem duplex expected, onaverage, from a set of loops of comparable length consisting of randomlyselected sequences of nucleotides. For example, a tetraL can confer aT_(m) of at least about 50° C., at least about 55° C., at least about56° C., at least about 58° C., at least about 60° C., at least about 65°C., or at least about 75° C. in 10 mM NaHPO₄ to a hairpin comprising aduplex of at least 2 base pairs (bp) in length. A tetraL also maystabilize a bp in an adjacent stem duplex by stacking interactions.Additionally, interactions among the nucleotides in a tetraloop include,but are not limited to, non-Watson-Crick base pairing, stackinginteractions, hydrogen bonding, and contact interactions (Cheong et al.(1990) NATURE 346:680-82; Heus & Pardi (1991) SCIENCE 253:191-94). Here,a tetraL can include or can have about 3 to about 6 nucleotides, andtypically is about 4 to about 5 nucleotides. A tetraL therefore can have3, 4, 5, or 6 nucleotides, which may or may not be modified (e.g., whichmay or may not be conjugated to a targeting moiety), especially 4nucleotides. Any nucleotide may be used in the tetraL, and standardIUPAC-IUB symbols for such nucleotides may be used as described inCornish-Bowden (1985) NUCLEIC ACIDS RES. 13:3021-30. For example, theletter “N” may be used to mean that any base may be in that position,the letter “R” may be used to show that A (adenine) or G (guanine) maybe in that position, and “B” may be used to show that C (cytosine), G(guanine), or T (thymine) may be in that position. Examples of tetraLinclude the UNCG family of tetraloops (e.g., UUCG), the GNRA family oftetraloops (e.g., GAAA) and the CUUG tetraloop (Woese et al. (1990)PROC. NATL. ACAD. SCI. USA 87:8467-71; Antao et al. (1991) NUCLEIC ACIDSRES. 19:5901-05). Examples of DNA tetraloops include the d(GNNA) familyof tetraloops (e.g., d(GTTA)), the d(GNRA) family of tetraloops, thed(GNAB) family of tetraloops, the d(CNNG) family of tetraloops, and thed(TNCG) family of tetraloops (e.g., d(TTCG)). See, e.g., Nakano et al.(2002) BIOCHEM. 41:4281-92; and Shinji et al. (2000) NIPPON KAGAKKAIKOEN YOKOSHU 78:731. Here, the tetraL can be within a nicked tetraLstructure.

As used herein, “treat” or “treating” means an act of providing care toan individual in need thereof, for example, by administering atherapeutic agent (e.g., an oligonucleotide herein) to the individualfor purposes of improving the health and/or well-being of the individualwith respect to an existing a disease, disorder, or condition, or toprevent or decrease the likelihood of the occurrence of a disease,disorder, or condition. Treating also can involve reducing the frequencyor severity of at least one sign, symptom or contributing factor of adisease, disorder, or condition experienced by the individual.

Compositions

Oligonucleotide Inhibitors of SCAP Activity

I. SCAP Target Sequences: The oligonucleotides herein (e.g., anantisense strand of a ds oligonucleotide such as a RNAi oligonucleotide)are targeted to a target sequence within SCAP mRNA. For example, anoligonucleotide, or a portion, fragment, or strand thereof binds oranneals to a target sequence within a SCAP mRNA, thereby inhibiting SCAPactivity. In some embodiments, the oligonucleotide is targeted to a SCAPtarget sequence for inhibiting SCAP activity in vivo. In someembodiments, the amount or extent of inhibition of SCAP activity by anoligonucleotide targeted to a SCAP target sequence correlates with thepotency of the oligonucleotide. In some embodiments, the amount orextent of inhibition of SCAP activity by an oligonucleotide targeted toa SCAP target sequence correlates with the amount or extent oftherapeutic benefit in an individual having or suspected of having adisease, disorder, or condition associated with SCAP activity treatedwith the oligonucleotide.

Through examining and analyzing the nucleotide sequence of SCAP mRNAs,including mRNAs of multiple different species (e.g., human, mouse and/ormonkey; see, e.g., Example 2) and because of in vitro and in vivotesting (see, e.g., Examples 3 and 4), it is shown herein that certainnucleotide sequences of SCAP mRNA are more amenable than others tooligonucleotide-based inhibition of SCAP activity and are thus useful astarget sequences for the oligonucleotides herein. In some embodiments, asense strand of an oligonucleotide herein (e.g., a ds oligonucleotidesuch as a RNAi oligonucleotide; e.g., in Table 3) includes a SCAP targetsequence. In some instances, a portion or region of the sense strand ofRNAi oligonucleotide herein (e.g., in Table 3) includes a SCAP targetsequence. In some embodiments, a SCAP target sequence comprises, orconsists of, a sequence of any one of SEQ ID NOs: 777 to 783 or any oneof the odd numbers of SEQ ID NOs: 785 to 1168 (especially any one of SEQID NOs: 915, 923, 997, 1049, 1097, 1109, and 1137).

II. SCAP mRNA Targeting Sequences: In some embodiments, theoligonucleotide herein (e.g., an antisense strand of a dsoligonucleotide such as a RNAi oligonucleotide) has a region ofcomplementarity to SCAP mRNA (e.g., within a target sequence of SCAPmRNA) for targeting SCAP mRNA in cells and inhibiting SCAP activity. Insome embodiments, the oligonucleotide comprises a SCAP targetingsequence (e.g., an antisense strand of a ds oligonucleotide) having aregion of complementarity that binds or anneals to a SCAP mRNA targetsequence by complementary (Watson-Crick) base pairing. The targetingsequence or region of complementarity is of a suitable length and basecontent to enable binding or annealing of the oligonucleotide (or astrand thereof) to a SCAP mRNA for inhibiting its expression. In someembodiments, the targeting sequence or region of complementarity is atleast about 12, at least about 13, at least about 14, at least about 15,at least about 16, at least about 17, at least about 18, at least about19, at least about 20, at least about 21, at least about 22, at leastabout 23, at least about 24, at least about 25, at least about 26, atleast about 27, at least about 28, at least about 29, or at least about30 nucleotides in length. Alternatively, the targeting sequence orregion of complementarity is about 12 to about 30 (e.g., 12 to 30, 12 to22, 15 to 25, 17 to 21, 18 to 27, 19 to 27, or 15 to 30) nucleotides inlength. Alternatively, the targeting sequence or region ofcomplementarity is about 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, or 30 nucleotides in length. In certainembodiments, the targeting sequence or region of complementarity is 18nucleotides in length. In certain embodiments, the targeting sequence orregion of complementarity is 19 nucleotides in length. In certainembodiments, the targeting sequence or region of complementarity is 20nucleotides in length. In certain embodiments, the targeting sequence orregion of complementarity is 21 nucleotides in length. In certainembodiments, the targeting sequence or region of complementarity is 22nucleotides in length. In certain embodiments, the targeting sequence orregion of complementarity is 23 nucleotides in length. In certainembodiments, the targeting sequence or region of complementarity is 24nucleotides in length.

In some embodiments, the oligonucleotide herein comprises a targetingsequence or a region of complementarity (e.g., an antisense strand of ads oligonucleotide) that is fully complementary to a SCAP mRNA targetingsequence. In some embodiments, the targeting sequence or region ofcomplementarity is partially complementary to a SCAP mRNA targetingsequence. In some embodiments, the oligonucleotide comprises a targetingsequence or region of complementarity that is fully complementary to asequence of any one of SEQ ID NOs: 777 to 783. In some embodiments, theoligonucleotide comprises a targeting sequence or region ofcomplementarity that is partially complementary to a sequence of any oneof SEQ ID NOs: 777 to 783.

Alternatively, in some embodiments, the oligonucleotide herein comprisesa targeting sequence or region of complementarity that is complementaryto a contiguous sequence of nucleotides comprising a SCAP mRNA, wherethe contiguous sequence of nucleotides is about 12 to about 30nucleotides in length (e.g., 12 to 30, 12 to 28, 12 to 26, 12 to 24, 12to 20, 12 to 18, 12 to 16, 14 to 22, 16 to 20, 18 to 20, or 18 to 19nucleotides in length). In some embodiments, the oligonucleotidecomprises a targeting sequence or region of complementarity that iscomplementary to a contiguous sequence of nucleotides comprising a SCAPmRNA, where the contiguous sequence of nucleotides is 10, 11, 12, 13,14, 15, 16, 17, 18, 19, or 20 nucleotides in length. In someembodiments, the oligonucleotide comprises a targeting sequence orregion of complementarity that is complementary to a contiguous sequenceof nucleotides comprising a SCAP mRNA, where the contiguous sequence ofnucleotides is 19 nucleotides in length. In some embodiments, theoligonucleotides comprise a targeting sequence or region ofcomplementarity that is complementary to a contiguous sequence ofnucleotides comprising a SCAP mRNA, where the contiguous sequence ofnucleotides is 20 nucleotides in length. In other embodiments, theoligonucleotides comprise a targeting sequence or a region ofcomplementarity that is complementary to a contiguous sequence ofnucleotides of any one of SEQ ID NOs: 777 to 783, optionally where thecontiguous sequence of nucleotides is 19 nucleotides in length.

With regard to the targeting sequence or region of complementarity ofthe oligonucleotides herein, it is complementary to contiguousnucleotides of a sequence as set forth in any one of SEQ ID NOs: 777 to783 and spans the entire length of an antisense strand. In someembodiments, the region of complementarity of the oligonucleotide iscomplementary to contiguous nucleotides of a sequence as set forth inany one of SEQ ID NOs: 777 to 783 and spans a portion of the entirelength of an antisense strand. In some additional embodiments, theoligonucleotide includes a region of complementarity (e.g., on anantisense strand of a ds oligonucleotide) that is at least partially(e.g., fully) complementary to a contiguous stretch of nucleotidesspanning nucleotides 1-20, 1-19, 1-18, etc. of a sequence as set forthin any one of SEQ ID NOs: 777 to 783.

Alternatively, the oligonucleotide comprises a targeting sequence orregion of complementarity having one or more base pair (bp) mismatcheswith the corresponding SCAP mRNA target sequence. In some embodiments,the targeting sequence or region of complementarity is up to about 1, upto about 2, up to about 3, up to about 4, up to about 5, etc. mismatcheswith the corresponding SCAP target sequence, provided that the abilityof the targeting sequence or region of complementarity to bind or annealto a SCAP mRNA under appropriate hybridization conditions and/or theability of the oligonucleotide to reduce or inhibit SCAP activity ismaintained. Stated differently, the targeting sequence or region ofcomplementarity is no more than 1, no more than 2, no more than 3, nomore than 4, or no more than 5 mismatches with the corresponding SCAPtarget sequence provided that the ability of the targeting sequence orregion of complementarity to bind or anneal to a SCAP mRNA underappropriate hybridization conditions and/or the ability of theoligonucleotide to reduce or inhibit SCAP activity is maintained. Insome embodiments, the oligonucleotide comprises a targeting sequence orregion of complementarity having 1 mismatch with the correspondingtarget sequence. In some embodiments, the oligonucleotide comprises atargeting sequence or region of complementarity having 2 mismatches withthe corresponding target sequence. In some embodiments, theoligonucleotide comprises a targeting sequence or a region ofcomplementarity having 3 mismatches with the corresponding targetsequence. In some embodiments, the oligonucleotide comprises a targetingsequence or region of complementarity having 4 mismatches with thecorresponding target sequence. In some embodiments, the oligonucleotidecomprises a targeting sequence or region of complementarity having 5mismatches with the corresponding target sequence. In other embodiments,the oligonucleotide comprises a targeting sequence or a region ofcomplementarity more than one mismatch (e.g., 2, 3, 4, 5 or moremismatches) with the corresponding target sequence, where at least 2(e.g., all) of the mismatches are positioned consecutively (e.g., 2, 3,4, 5 or more mismatches in a row), or where the mismatches areinterspersed in any position throughout the targeting sequence or regionof complementarity. In other embodiments, the oligonucleotide comprisesa targeting sequence or region of complementarity more than one mismatch(e.g., 2, 3, 4, 5 or more mismatches) with the corresponding targetsequence, where at least 2 (e.g., all) of the mismatches are positionedconsecutively (e.g., 2, 3, 4, 5 or more mismatches in a row), or whereat least one or more non-mismatched bp is located between themismatches, or a combination thereof.

III. Types of Oligonucleotides: A variety of oligonucleotide typesand/or structures are useful for targeting SCAP mRNA including, but notlimited to, RNAi oligonucleotides, ASOs, miRNAs, etc. Any of theoligonucleotide types described herein or elsewhere are contemplated foruse as a framework to incorporate a targeting sequence herein for thepurposes of inhibiting SCAP activity. In some embodiments, theoligonucleotide herein inhibits SCAP activity by engaging with RNAipathways upstream or downstream of Dicer involvement. For example, RNAioligonucleotides have been developed with each strand having sizes ofabout 19-25 nucleotides with at least one 3′ overhang of 1 to 5nucleotides (see, e.g., U.S. Pat. No. 8,372,968). Longeroligonucleotides also have been developed that are processed by Dicer togenerate active RNAi products (see, e.g., U.S. Pat. No. 8,883,996).Further work produced extended ds oligonucleotides where at least oneend of at least one strand is extended beyond a duplex targeting region,including structures where one of the strands includes athermodynamically stabilizing tetraL (see, e.g., U.S. Pat. Nos.8,513,207 and 8,927,705, as well as Intl. Patent Application PublicationNo. WO 2010/033225). Such structures include ss extensions (on one orboth sides of the molecule) as well as ds extensions.

The oligonucleotides herein engage with the RNAi pathway downstream ofthe involvement of Dicer (e.g., Dicer cleavage). In some embodiments,the oligonucleotide has an overhang (e.g., of 1, 2, or 3 nucleotides inlength) in the 3′ end of the sense strand. In some embodiments, theoligonucleotide (e.g., siRNA) includes a 21-nucleotide antisense strandthat is antisense to a target mRNA (e.g., SCAP mRNA) and a complementarysense strand, in which both strands anneal to form a 19-bp duplex and 2nucleotide overhangs at either or both 3′ ends. Longer oligonucleotidedesigns also are contemplated, including oligonucleotides having anantisense strand of 23 nucleotides and a sense strand of 21 nucleotides,where there is a blunt end on the right side of the molecule (3′ end ofsense strand/5′ end of antisense strand) and a two nucleotide 3′antisense strand overhang on the left side of the molecule (5′ end ofthe sense strand/3′ end of the antisense strand). In such molecules,there is a 21 bp duplex region. See, e.g., U.S. Pat. Nos. 9,012,138;9,012,621 and 9,193,753.

The oligonucleotide herein comprises sense and antisense strands thatare both in the range of about 17 to about 26 (e.g., 17 to 26, 20 to 25,or 21-23) nucleotides in length. In some embodiments, theoligonucleotide comprises a sense and antisense strand that are both inthe range of about 19 to about 22 nucleotides in length. In someembodiments, the sense and antisense strands are of equal length. Insome embodiments, the oligonucleotide comprises sense and antisensestrands, such that there is a 3′ overhang on either the sense strand orthe antisense strand, or both the sense and antisense strand. In someembodiments, for an oligonucleotide having sense and antisense strandsthat are both in the range of about 21 to about 23 nucleotides inlength, a 3′ overhang on the sense, antisense or both sense andantisense strands is 1 or 2 nucleotides in length. In some embodiments,the oligonucleotide comprises an antisense strand of 22 nucleotides anda sense strand of 20 nucleotides, where there is a blunt end on theright side of the molecule (3′ end of sense strand/5′ end of antisensestrand) and a 2 nucleotide 3′ antisense strand overhang on the left sideof the molecule (5′ end of the sense strand/3′ end of the antisensestrand). In such molecules, there is a 20-bp duplex region.

Other oligonucleotide designs for use herein include: 16-mer siRNAs(see, e.g., “NUCLEIC ACIDS IN CHEMISTRY & BIOLOGY,” Blackburn (ed.),Royal Society of Chemistry, 2006), shRNAs (e.g., having 19 bp or shorterstems; see, e.g., Moore et al. (2010) METHODS MOL. BIOL. 629:141-58),blunt siRNAs (e.g., of 19 bps in length; see, e.g., Kraynack & Baker(2006) RNA 12:163-76), asymmetrical siRNAs (aiRNA; see, e.g., Sun et al.(2008) NAT. BIOTECHNOL. 26:1379-82), asymmetric shorter-duplex siRNA(see, e.g., Chang et al. (2009) MOL. THER. 17:725-32), fork siRNAs (see,e.g., Hohjoh (2004) FEBS LETT. 557:193-98), ss siRNAs (see, e.g., Elsner(2012) NAT. BIOTECHNOL. 30:1063), dumbbell-shaped circular siRNAs (see,e.g., Abe et al. (2007) J. AM. CHEM. SOC. 129:15108-09), and smallinternally segmented interfering RNA (sisiRNA; see, e.g., Bramsen et al.(2007) NUCLEIC ACIDS RES. 35:5886-97). Further non-limiting examples ofoligonucleotide structures that may be used herein to reduce or inhibitSCAP activity are miRNA, shRNA, and short siRNA (see, e.g., Hamilton etal. (2002) EMBO J. 21:4671-79; see also, U.S. Pat. No. 7,659,389).

Alternatively, the oligonucleotide herein is ss. Such structuresinclude, but are not limited to, ss RNAi molecules. Recent efforts havedemonstrated the activity of ss RNAi molecules (see, e.g., Matsui et al.(2016) MOL. THER. 24:946-55). In some embodiments, the oligonucleotideis an ASOs. An ASO is a ss oligonucleotide that has a nucleobasesequence that, when written or depicted in the 5′ to 3′ direction,includes a reverse complement of a targeted segment of a particularnucleic acid and is suitably modified (e.g., as a gapmer) to induceRNaseH-mediated cleavage of its target RNA in cells or (e.g., as amixmer) so as to inhibit translation of the target mRNA in cells. ASOsfor use herein are modified in any suitable manner known in the artincluding, for example, as shown in U.S. Pat. No. 9,567,587 (including,for example, length, sugar moieties of the nucleobase (pyrimidine,purine), and alterations of the heterocyclic portion of the nucleobase).Further, ASOs have been used for decades to reduce expression ofspecific target genes (see, e.g., Bennett et al. (2017) ANNU. REV.PHARMACOL. 57:81-105).

IV. ds RNAi Oligonucleotides: ds RNAi oligonucleotides for targetingSCAP mRNA and inhibiting SCAP activity (e.g., via the RNAi pathway)comprise a sense strand and an antisense strand. In some embodiments,the sense strand and antisense strand are separate strands and are notcovalently linked. In some embodiments, the sense strand and antisensestrand are covalently linked.

In some embodiments, the sense strand comprises a first region (R1) anda second region (R2), where R2 comprises a first subregion (S1), a triLor a L, and a second subregion (S2), where triL or L is located betweenS1 and S2, and where S1 and S2 form a second duplex (D2). D2 has variouslengths. In some embodiments, D2 is about 1 to about 6 bp in length. Inother embodiments, D2 is 2-6, 3-6, 4-6, 5-6, 1-5, 2-5, 3-5 or 4-5 bp inlength. In other embodiments, D2 is 1, 2, 3, 4, 5 or 6 bp in length. Incertain embodiments, D2 is 6 bp in length.

In some embodiments, R1 of the sense strand and the antisense strandforms a first duplex (D1). In some embodiments, D1 is at least about 15(e.g., at least 15, at least 16, at least 17, at least 18, at least 19,at least 20 or at least 21) nucleotides in length. In other embodiments,D1 is about 12 to about 30 nucleotides in length (e.g., 12 to 30, 12 to27, 15 to 22, 18 to 22, 18 to 25, 18 to 27, 18 to 30 or 21 to 30nucleotides in length). In other embodiments, D1 is at least 12nucleotides in length (e.g., at least 12, at least 15, at least 20, atleast 25 or at least 30 nucleotides in length). In other embodiments, D1is 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29 or 30 nucleotides in length. In certain embodiments, D1 is 20nucleotides in length. In some embodiments, D1 does not span the entirelength of the sense strand and/or antisense strand. In otherembodiments, D1 spans the entire length of either the sense strand orantisense strand or both. In certain embodiments, D1 spans the entirelength of both the sense strand and the antisense strand.

In certain embodiments, the disclosure describes RNAi oligonucleotidesfor reducing or inhibiting SCAP activity that include a sense strandcomprising, or alternatively consisting of, a sequence as set forth inTable 3 (e.g., any one of the odd numbers of SEQ ID NOs: 9 to 392),especially SEQ ID NOs: 139, 147, 221, 273, 321, 333, and 361.

In certain embodiments, the disclosure describes RNAi oligonucleotidesfor reducing or inhibiting SCAP activity that include an antisensestrand comprising, or alternatively consisting of, a sequence as setforth in Table 3 (e.g., any one of the even numbers of SEQ ID NOs: 9 to392), especially SEQ ID NOs: 140, 148, 222, 274, 322, 334, and 362.

In certain other embodiments, the RNAi oligonucleotide includes a sensestrand comprising, or alternatively consisting of, a nucleotide sequenceof any one of SEQ ID NOs: 139, 147, 221, 273, 321, 333 and 361, and anantisense strand comprising, or alternatively consisting of, anucleotide sequence of any one of SEQ ID NOs: 140, 148, 222, 274, 322,334 and 362.

In certain embodiments, the sense strand and the antisense strand of aRNAi oligonucleotide, respectively, are selected from:

-   -   (a) SEQ ID NOs: 139 and 140,    -   (b) SEQ ID NOs: 147 and 148,    -   (c) SEQ ID NOs: 221 and 222,    -   (d) SEQ ID NOs: 273 and 274,    -   (e) SEQ ID NOs: 321 and 322,    -   (f) SEQ ID NOs: 333 and 334, and    -   (g) SEQ ID NOs: 361 and 362.

In certain additional embodiments, the RNAi oligonucleotide includes asense strand comprising, or alternatively consisting of, a nucleotidesequence of SEQ ID NO: 147 or 333, and an antisense strand comprising,or alternatively consisting of, a nucleotide sequence of SEQ ID NO: 148or 334. Alternatively, the sense strand is SEQ ID NO: 147 and theantisense strand is SEQ ID NO: 148. Alternatively, the sense strand isSEQ ID NO: 333 and the antisense strand is SEQ ID NO: 334.

In some embodiments, the RNAi oligonucleotide includes a sense strandcomprising, or alternatively consisting of, a nucleotide sequence as setforth in Table 4 (e.g., any one of the odd numbers of SEQ ID NOs: 393 to776), especially SEQ ID NOs: 523, 531, 605, 657, 705, 717, and 745.

In certain embodiments, the RNAi oligonucleotide includes an antisensestrand comprising, or alternatively consisting of, a nucleotide sequenceas set forth in Table 4 (e.g., any one of the even numbers of SEQ IDNOs: 393 to 776), especially SEQ ID NOs: 524, 532, 606, 658, 706, 718,and 746.

In certain other embodiments, the RNAi oligonucleotide includes a sensestrand comprising, or alternatively consisting of, a nucleotide sequenceof any one of SEQ ID NOs: 523, 531, 605, 657, 705, 717 and 745, and anantisense strand comprising, or alternatively consisting of, anucleotide sequence of any one of SEQ ID NOs: 524, 532, 606, 658, 706,718 and 746.

In certain embodiments, the sense strand, and the antisense strand ofthe RNAi oligonucleotide, respectively, are selected from:

-   -   (a′) SEQ ID NOs: 523 and 524,    -   (b′) SEQ ID NOs: 531 and 532,    -   (c′) SEQ ID NOs: 605 and 606,    -   (d′) SEQ ID NOs: 657 and 658,    -   (e′) SEQ ID NOs: 705 and 706,    -   (f′) SEQ ID NOs: 717 and 718, and    -   (g′) SEQ ID NOs: 745 and 746.

In certain additional embodiments, the RNAi oligonucleotide includes asense strand comprising, or alternatively consisting of, a nucleotidesequence of SEQ ID NO: 531 or 717, and an antisense strand comprising,or alternatively consisting of, a nucleotide sequence of SEQ ID NO: 532or 718. Alternatively, the sense strand is SEQ ID NO: 531 and theantisense strand is SEQ ID NO: 532. Alternatively, the sense strand isSEQ ID NO: 717 and the antisense strand is SEQ ID NO: 718.

One of skill in the art appreciates that in some embodiments, thesequences presented in the Sequence Listing are referred to indescribing the structure of an oligonucleotide (e.g., a dsoligonucleotide such as a RNAi oligonucleotide) or other nucleic acid.In such embodiments, the actual oligonucleotide or other nucleic acidhas one or more alternative nucleotides (e.g., an RNA counterpart of aDNA nucleotide or a DNA counterpart of an RNA nucleotide) and/or one ormore modified nucleotides and/or one or more modified internucleotidelinkages and/or one or more other modification when compared with thespecified sequence while retaining essentially same or similarcomplementary properties as the specified sequence.

In some embodiments, an oligonucleotide herein (e.g., a dsoligonucleotide such as a RNAi oligonucleotide) includes a 25-nucleotidesense strand and a 27-nucleotide antisense strand that when acted uponby a Dicer enzyme results in an antisense strand that is incorporatedinto the mature RISC. In other embodiments, the sense strand of the dsoligonucleotide is longer than 25 nucleotides (e.g., 26, 27, 28, 29, or30 nucleotides). In other embodiments, the sense strand of the dsoligonucleotide is longer than 27 nucleotides (e.g., 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, or 40 nucleotides).

In some embodiments, the oligonucleotide has one 5′ end that isthermodynamically less stable when compared to the other 5′ end. In someembodiments, the oligonucleotide is asymmetric and includes a blunt endat the 3′ end of a sense strand and a 3′ overhang at the 3′ end of anantisense strand. In some embodiments, the 3′ overhang on the antisensestrand is about 1 to about 8 nucleotides in length (e.g., 1, 2, 3, 4, 5,6, 7, or 8 nucleotides in length). Typically, a ds oligonucleotide forRNAi has a two-nucleotide overhang on the 3′ end of the antisensestrand. However, other overhangs are possible. In some embodiments, anoverhang is a 3′ overhang having a length of between about 1 to about 6nucleotides, optionally 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 6, 2 to 5,2 to 4, 2 to 3, 3 to 6, 3 to 5, 3 to 4, 4 to 6, 4 to 5, 5 to 6nucleotides, or 1, 2, 3, 4, 5, or 6 nucleotides. However, in otherembodiments, the overhang is a 5′ overhang comprising a length ofbetween about 1 to about 6 nucleotides, optionally 1 to 5, 1 to 4, 1 to3, 1 to 2, 2 to 6, 2 to 5, 2 to 4, 2 to 3, 3 to 6, 3 to 5, 3 to 4, 4 to6, 4 to 5, 5 to 6 nucleotides, or 1, 2, 3, 4, 5, or 6 nucleotides.

In some embodiments, 2 terminal nucleotides on the 3′ end of anantisense strand are modified. In some embodiments, the 2 terminalnucleotides on the 3′ end of the antisense strand are complementary withthe target mRNA (e.g., SCAP mRNA). In other embodiments, the 2 terminalnucleotides on the 3′ end of the antisense strand are not complementarywith the target mRNA. In some embodiments, the 2 terminal nucleotides onthe 3′ end of the antisense strand of an oligonucleotide herein areunpaired. In some embodiments, 2 terminal nucleotides on each 3′ end ofan oligonucleotide in the nicked tetraL structure are GG. Typically, oneor both of the 2 terminal GG nucleotides on each 3′ end of a dsoligonucleotide are not complementary with the target mRNA.

In some embodiments, there is one or more (e.g., 1, 2, 3, 4, or 5)mismatch(s) between the sense and antisense strand. If there is morethan one mismatch between the sense and antisense strand, they may bepositioned consecutively (e.g., 2, 3, or more in a row), or interspersedthroughout the region of complementarity. In some embodiments, the 3′end of the sense strand contains one or more mismatches. In certainembodiments, two mismatches are incorporated at the 3′ end of the sensestrand. In some embodiments, base mismatches, or destabilization ofsegments at the 3′ end of the sense strand of the oligonucleotideimproves or increases the potency of the ds oligonucleotide.

In some embodiments, there is one or more (e.g., 1, 2, 3, 4, or 5)mismatch(s) between a sense and antisense strand comprising anoligonucleotide herein (e.g., a ds oligonucleotide such as a RNAioligonucleotide). If there is more than one mismatch between a sense andantisense strand, they may be positioned consecutively (e.g., 2, 3 ormore in a row), or interspersed throughout the region ofcomplementarity. In some embodiments, the 3′ end of the sense strandcomprises one or more mismatches. In some embodiments, two (2)mismatches are incorporated at the 3′ end of the sense strand. In someembodiments, base mismatches, or destabilization of segments at the 3′end of the sense strand of an oligonucleotide herein improves orincreases the potency of the oligonucleotide. In some embodiments, thesense and antisense strands of an oligonucleotide herein comprisenucleotides sequences selected from Table 3, optionally from the groupconsisting of:

-   -   (a) SEQ ID NOs: 139 and 140,    -   (b) SEQ ID NOs: 147 and 148,    -   (c) SEQ ID NOs: 221 and 222,    -   (d) SEQ ID NOs: 273 and 274,    -   (e) SEQ ID NOs: 321 and 322,    -   (f) SEQ ID NOs: 333 and 334, and    -   (g) SEQ ID NOs: 361 and 362,        wherein there is one or more (e.g., 1, 2, 3, 4 or 5) mismatch(s)        between the sense and antisense strands.

A. Sense Strands: The oligonucleotides herein (e.g., a dsoligonucleotide such as a RNAi oligonucleotide) include a sense strandsequence including a sequence as set forth in the sense strands of Table3 or Table 4. In some embodiments, the oligonucleotide includes a sensestrand that having at least about 12 (e.g., at least 12, at least 13, atleast 14, at least 15, at least 16, at least 17, at least 18, at least19, at least 20, at least 21, at least 22, or at least 23) contiguousnucleotides of a sequence as set forth in in any one of SEQ ID NOs: 139,147, 221, 273, 321, 333 and 361, or a sense strand having a nucleotidesequence of any one of SEQ ID NOs: 140, 148, 222, 274, 322, 334 and 362.

Further, the oligonucleotide can include a sense strand of up to about50 nucleotides in length (e.g., up to 50, up to 40, up to 36, up to 30,up to 27, up to 25, up to 21, up to 19, up to 17, or up to 12nucleotides in length). In some embodiments, the oligonucleotide canhave a sense strand of at least about 12 nucleotides in length (e.g., atleast 12, at least 15, at least 19, at least 21, at least 25, at least27, at least 30, at least 36, or at least 38 nucleotides in length).Alternatively, the oligonucleotide can have a sense strand in a range ofabout 12 to about 40 (e.g., 12 to 40, 12 to 36, 12 to 32, 12 to 28, 15to 40, 15 to 36, 15 to 32, 15 to 28, 17 to 21, 17 to 25, 19 to 27, 19 to30, 20 to 40, 22 to 40, 25 to 40, or 32 to 40) nucleotides in length. Incertain embodiments, the oligonucleotide can have a sense strand of 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 nucleotides in length.

In some embodiments, the sense strand comprises a stem-loop structure atits 3′ end. In other embodiments, the sense strand comprises a stem-loopstructure at its 5′ end. In some embodiments, the stem-loop is formed byintrastrand base pairing. In additional embodiments, the stem is aduplex of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 bp inlength. In some embodiments, the stem of the stem-loop comprises aduplex of 2 nucleotides in length. In some embodiments, the stem of thestem-loop comprises a duplex of 3 nucleotides in length. In someembodiments, the stem of the stem-loop comprises a duplex of 4nucleotides in length. In some embodiments, the stem of the stem-loopcomprises a duplex of 5 nucleotides in length. In some embodiments, thestem of the stem-loop comprises a duplex of 6 nucleotides in length. Insome embodiments, the stem of the stem-loop comprises a duplex of 7nucleotides in length. In some embodiments, the stem of the stem-loopcomprises a duplex of 8 nucleotides in length. In some embodiments, thestem of the stem-loop comprises a duplex of 9 nucleotides in length. Insome embodiments, the stem of the stem-loop comprises a duplex of 10nucleotides in length. In some embodiments, the stem of the stem-loopcomprises a duplex of 11 nucleotides in length. In some embodiments, thestem of the stem-loop comprises a duplex of 12 nucleotides in length. Insome embodiments, the stem of the stem-loop comprises a duplex of 13nucleotides in length. In some embodiments, the stem of the stem-loopcomprises a duplex of 14 nucleotides in length.

In some embodiments, the stem-loop provides the oligonucleotideprotection against degradation (e.g., enzymatic degradation) andfacilitates or improves targeting and/or delivery to a target cell,tissue, or organ (e.g., the liver), or both. For example, the L of thestem-loop provides nucleotides having one or more modifications thatfacilitate, improve, or increase targeting to a target mRNA (e.g., aSCAP mRNA), inhibiting of target gene expression (e.g., SCAP activity),and/or delivering to a target cell, tissue, or organ (e.g., the liver),or both. In some embodiments, the stem-loop itself or modification(s) tothe stem-loop do not substantially affect the inherent gene expressioninhibition activity of the oligonucleotide, but facilitates, improves,or increases stability (e.g., provides protection against degradation)and/or delivery of the oligonucleotide to a target cell, tissue, ororgan (e.g., the liver). In certain embodiments, the oligonucleotidecomprises a sense strand including (e.g., at its 3′ end) a stem-loop setforth as: S1-L-S2, in which S1 is complementary to S2, and in which Lforms a ss loop between S1 and S2 of up to about 10 nucleotides inlength (e.g., 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides in length). In someembodiments, L is 3 nucleotides in length (referred to herein as“triloop” or “triL”). In some embodiments, L is 4 nucleotides in length(referred to herein as “tetraloop” or “tetraL”). In some embodiments, Lis 5 nucleotides in length. In some embodiments, L is 6 nucleotides inlength. In some embodiments, L is 7 nucleotides in length. In someembodiments, L is 8 nucleotides in length. In some embodiments, L is 9nucleotides in length. In some embodiments, L is 10 nucleotides inlength. In certain embodiments, L is 4 nucleotides in length. FIG. 1depicts a non-limiting example of such an oligonucleotide. In someembodiments L of the stem-loop having the structure S1-L-S2 as describedabove is a tetraL (e.g., within a nicked tetraL structure). In someembodiments, the tetraL comprises ribonucleotides, deoxyribonucleotides,modified nucleotides, delivery ligands and combinations thereof. Incertain embodiments, the tetraL comprises the sequence 5′-GAAA-3′. Inother certain embodiments, the stem-loop comprises the sequence5′-GCAGCCGAAAGGCUGC-3′ (SEQ ID NO: 784).

In some embodiments, the oligonucleotide comprises a targeting sequenceor a region of complementary that is complementary to a contiguoussequence of nucleotides of any one of the odd numbers of SEQ ID NOs:785-1168, especially any one of SEQ ID NOs: 915, 923, 997, 1049, 1097,1109, and 1137, and the oligonucleotide comprises a sense strandcomprising (e.g., at its 3′ end) a stem-loop set forth as: S1-L-S2, inwhich S1 is complementary to S2, and in which L forms a single-strandedloop between S1 and S2 of up to about 10 nucleotides in length (e.g., 3,4, 5, 6, 7, 8, 9, or 10 nucleotides in length). In some embodiments, theoligonucleotide comprises a targeting sequence or a region ofcomplementary that is complementary to a contiguous sequence ofnucleotides of any one of the odd numbers of SEQ ID NOs: 785-1168,especially any one of SEQ ID NOs: 915, 923, 997, 1049, 1097, 1109, and1137, and the oligonucleotide comprises a sense strand comprising (e.g.,at its 3′ end) a stem-loop set forth as: S1-L-S2, in which S1 iscomplementary to S2, and in which L forms a single-stranded loop betweenS1 and S2 of 4 nucleotides in length.

In some embodiments, L of a stem-loop having the structure S1-L-S2 asdescribed herein is a triL. In some embodiments, the oligonucleotidecomprises a targeting sequence or a region of complementary that iscomplementary to a contiguous sequence of nucleotides of any one of theodd numbers of SEQ ID NOs: 785-1168, especially any one of SEQ ID NOs:915, 923, 997, 1049, 1097, 1109, and 1137 and a triL. In someembodiments, the triL comprises ribonucleotides, deoxyribonucleotides,modified nucleotides, ligands (e.g., delivery ligands), and combinationsthereof.

In some embodiments, L of a stem-loop having the structure S1-L-S2 asdescribed above is a tetraL. In some embodiments, the oligonucleotidecomprises a targeting sequence or a region of complementary that iscomplementary to a contiguous sequence of nucleotides of any one of theodd numbers of SEQ ID NOs: 785-1168, especially any one of SEQ ID NOs:915, 923, 997, 1049, 1097, 1109, and 1137 and a tetraL. In someembodiments, the tetraL comprises ribonucleotides, deoxyribonucleotides,modified nucleotides, ligands (e.g., delivery ligands), and combinationsthereof.

B. Antisense Strands: The oligonucleotides herein (e.g., a dsoligonucleotide such as a RNAi oligonucleotide) include an antisensestrand including a sequence as set forth in the antisense strands ofTable 3 (unmodified) or Table 4 (modified). In some embodiments, theoligonucleotide includes an antisense strand having at least about 12(e.g., at least 12, at least 13, at least 14, at least 15, at least 16,at least 17, at least 18, at least 19, at least 20, at least 21, atleast 22, or at least 23) contiguous nucleotides of a sequence as setforth in any one of SEQ ID NOs: 139, 147, 221, 273, 321, 333, and 361,or an antisense strand having a nucleotide sequence of any one of SEQ IDNOs: 140, 148, 222, 274, 322, 334, and 362.

Further, the oligonucleotide can include an antisense strand of up toabout 50 nucleotides in length (e.g., up to 50, up to 40, up to 35, upto 30, up to 27, up to 25, up to 21, up to 19, up to 17 or up to 12nucleotides in length). In some embodiments, an oligonucleotidecomprises an antisense strand of at least about 12 nucleotides in length(e.g., at least 12, at least 15, at least 19, at least 21, at least 22,at least 25, at least 27, at least 30, at least 35 or at least 38nucleotides in length). In some embodiments, an oligonucleotidecomprises an antisense strand in a range of about 12 to about 40 (e.g.,12 to 40, 12 to 36, 12 to 32, 12 to 28, 15 to 40, 15 to 36, 15 to 32, 15to 28, 17 to 22, 17 to 25, 19 to 27, 19 to 30, 20 to 40, 22 to 40, 25 to40 or 32 to 40) nucleotides in length. In some embodiments, anoligonucleotide comprises antisense strand of 15 to 30 nucleotides inlength. In some embodiments, an antisense strand of any one of theoligonucleotides disclosed herein is of 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39 or 40 nucleotides in length. In some embodiments, anoligonucleotide comprises an antisense strand of 22 nucleotides inlength.

In some embodiments, the oligonucleotide comprises an antisense strandcomprising or consisting of a sequence as set forth in Table 3 (e.g.,any one of the even numbers of SEQ ID NOs: 9 to 392). In someembodiments, an oligonucleotide herein comprises an antisense strandcomprising at least about 12 (e.g., at least 12, at least 13, at least14, at least 15, at least 16, at least 17, at least 18, at least 19, atleast 20, at least 21, at least 22 or at least 23) contiguousnucleotides of a sequence as set forth in Table 3 (e.g., any one of theeven numbers of SEQ ID NOs: 9 to 392). In some embodiments, anoligonucleotide disclosed herein for targeting SCAP comprises anantisense strand comprising or consisting of a sequence as set forth asset forth in Table 3 (e.g., any one of the even numbers of SEQ ID NOs: 9to 392), especially any one of SEQ ID NOs: 140, 148, 222, 274, 322, 334,and 362. In some embodiments, an oligonucleotide herein comprises anantisense strand comprising at least about 12 (e.g., at least 12, atleast 13, at least 14, at least 15, at least 16, at least 17, at least18, at least 19, at least 20, at least 21, at least 22 or at least 23)contiguous nucleotides of a sequence as set forth in Table 4 (e.g., anyone of the even numbers of SEQ ID NOs: 393 to 776. In some embodiments,an oligonucleotide disclosed herein for targeting SCAP comprises anantisense strand comprising or consisting of a sequence as set forth inany one of SEQ ID NOs: 524, 532, 606, 658, 706, 718, and 746. In someembodiments, an oligonucleotide herein comprises an antisense strandcomprising at least about 12 (e.g., at least 12, at least 13, at least14, at least 15, at least 16, at least 17, at least 18, at least 19, atleast 20, at least 21, at least 22 or at least 23) contiguousnucleotides of a sequence as set forth in any one of SEQ ID NOs: SEQ IDNOs: 524, 532, 606, 658, 706, 718, and 746.

C. Duplex Length: The oligonucleotides herein (e.g., a dsoligonucleotide such as a RNAi oligonucleotide) include a duplex formedbetween the sense strand and the antisense strand, which is at leastabout 12 (e.g., at least 12, at least 13, at least 14, at least 15, atleast 16, at least 17, at least 18, at least 19, at least 20, or atleast 21) nucleotides in length. In some embodiments, the duplex formedbetween the sense strand and the antisense strand is in the range ofabout 12 to about 30 nucleotides in length (e.g., 12 to 30, 12 to 27, 12to 22, 15 to 25, 18 to 30, 18 to 22, 18 to 25, 18 to 27, 18 to 30, 19 to30, or 21 to 30 nucleotides in length). In some embodiments, the duplexformed between the sense strand and the antisense strand is 12, 13, 14,15, 16, 17, 18, 19, 29, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30nucleotides in length. In some embodiments, the duplex formed betweenthe sense strand and the antisense strand is 12 nucleotides in length.In some embodiments, the duplex formed between the sense strand and theantisense strand is 13 nucleotides in length. In some embodiments, theduplex formed between the sense strand and the antisense strand is 14nucleotides in length. In some embodiments, the duplex formed betweenthe sense strand and the antisense strand is 15 nucleotides in length.In some embodiments the duplex formed between the sense strand and theantisense strand is 16 nucleotides in length. In some embodiments, theduplex formed between the sense strand and the antisense strand is 17nucleotides in length. In some embodiments, the duplex formed betweenthe sense strand and the antisense strand is 18 nucleotides in length.In some embodiments, the duplex formed between the sense strand and theantisense strand is 19 nucleotides in length. In some embodiments, theduplex formed between the sense strand and the antisense strand is 20nucleotides in length. In some embodiments, the duplex formed betweenthe sense strand and the antisense strand is 21 nucleotides in length.In some embodiments, the duplex formed between the sense strand and theantisense strand is 22 nucleotides in length. In some embodiments, theduplex formed between the sense strand and the antisense strand is 23nucleotides in length. In some embodiments, the duplex formed betweenthe sense strand and the antisense strand is 24 nucleotides in length.In some embodiments, the duplex formed between the sense strand and theantisense strand is 25 nucleotides in length. In some embodiments, theduplex formed between the sense strand and the antisense strand is 26nucleotides in length. In some embodiments, the duplex formed betweenthe sense strand and the antisense strand is 27 nucleotides in length.In some embodiments, the duplex formed between the sense strand and theantisense strand is 28 nucleotides in length. In some embodiments, theduplex formed between the sense strand and the antisense strand is 29nucleotides in length. In some embodiments, the duplex formed betweenthe sense strand and the antisense strand is 30 nucleotides in length.In some embodiments, the duplex formed between the sense strand and theantisense strand does not span the entire length of the sense strandand/or antisense strand. In some embodiments, the duplex formed betweenthe sense strand and the antisense strand spans the entire length ofeither the sense strand or the antisense strand. In some embodiments,the duplex formed between the sense strand and the antisense strandspans the entire length of both the sense strand and the antisensestrand.

D. Oligonucleotide Termini: The oligonucleotides herein (e.g., a dsoligonucleotide such as a RNAi oligonucleotide) comprises a sense strandand an antisense strand, where a terminus of either or both strandscomprise a blunt end. In some embodiments, the oligonucleotide comprisessense and antisense strands that are separate strands that form anasymmetric duplex region having an overhang at a 3′ terminus of theantisense strand. In some embodiments, the oligonucleotide comprises asense strand and an antisense strand, where a terminus of either or bothstrands comprise an overhang comprising one or more nucleotides. In someembodiments, the one or more nucleotides comprising the overhang areunpaired nucleotides. In some embodiments, the oligonucleotide comprisesa sense strand and an antisense strand, wherein the 3′ terminus of thesense strand and the 5′ terminus of the antisense strand comprise ablunt end. In some embodiments, the oligonucleotide comprises a sensestrand and an antisense strand, wherein the 5′ terminus of the sensestrand and the 3′ terminus of the antisense strand comprise a blunt end.

In some embodiments, the oligonucleotide comprises a sense strand and anantisense strand, wherein the 3′ terminus of either or both strandscomprise a 3′ overhang comprising one or more nucleotides. In someembodiments, the oligonucleotide comprises a sense strand and anantisense strand, wherein the sense strand comprises a 3′ overhangcomprising one or more nucleotides. In some embodiments, theoligonucleotide comprises a sense strand and an antisense strand,wherein the antisense strand comprises a 3′ overhang comprising one ormore nucleotides. In some embodiments, the oligonucleotide comprises asense strand and an antisense strand, wherein both the sense strand andthe antisense strand comprises a 3′ overhang comprising one or morenucleotides.

In some embodiments, the 3′ overhang is about 1 to about 20 nucleotidesin length (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, or 20 nucleotides in length). In some embodiments,the 3′ overhang is about 1 to 19, 1 to 18, 1 to 17, 1 to 16, 1 to 15, 1to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 nucleotides in length. In someembodiments, the 3′ overhang is 1 nucleotide in length. In someembodiments, the 3′ overhang is 2 nucleotides in length. In someembodiments, the 3′ overhang is 3 nucleotides in length. In someembodiments, the 3′ overhang is 4 nucleotides in length. In someembodiments, the 3′ overhang is 5 nucleotides in length. In someembodiments, the 3′ overhang is 6 nucleotides in length. In someembodiments, the 3′ overhang is 7 nucleotides in length. In someembodiments, the 3′ overhang is 8 nucleotides in length. In someembodiments, the 3′ overhang is 9 nucleotides in length. In someembodiments, the 3′ overhang is 10 nucleotides in length. In someembodiments, the 3′ overhang is 11 nucleotides in length. In someembodiments, the 3′ overhang is 12 nucleotides in length. In someembodiments, the 3′ overhang is 13 nucleotides in length. In someembodiments, the 3′ overhang is 14 nucleotides in length. In someembodiments, the 3′ overhang is 15 nucleotides in length. In someembodiments, the 3′ overhang is 16 nucleotides in length. In someembodiments, the 3′ overhang is 17 nucleotides in length. In someembodiments, the 3′ overhang is 18 nucleotides in length. In someembodiments, the 3′ overhang is 19 nucleotides in length. In someembodiments, the 3′ overhang is 20 nucleotides in length.

In certain embodiments, the oligonucleotide comprises a sense strand andan antisense strand, where the antisense strand comprises a 3′ overhang.

V. Oligonucleotide Modifications: The oligonucleotides herein (e.g., ads oligonucleotide such as a RNAi oligonucleotide) include at least onemodification. The oligonucleotide may be modified in various ways toimprove or control specificity, stability, delivery, bioavailability,resistance from nuclease degradation, immunogenicity, base-pairingproperties, RNA distribution and cellular uptake and other featuresrelevant to therapeutic or research use.

In some embodiments, the modification is a modified sugar. In someembodiments, the modification is a 5′-terminal phosphate group. In someembodiments, the modification is a modified internucleotide linkage. Insome embodiments, the modification is a modified base. In someembodiments, the oligonucleotide comprises any one of the modificationsdescribed herein or any combination thereof. For example, in someembodiments, the oligonucleotide comprises at least one modified sugar,a 5′-terminal phosphate group, at least one modified internucleotidelinkage, and at least one modified base. In some embodiments, the senseand antisense strands of the oligonucleotide comprise nucleotidesequences selected from Table 3, optionally the group consisting of:

-   -   (a) SEQ ID NOs: 139 and 140,    -   (b) SEQ ID NOs: 147 and 148,    -   (c) SEQ ID NOs: 221 and 222,    -   (d) SEQ ID NOs: 273 and 274,    -   (e) SEQ ID NOs: 321 and 322,    -   (f) SEQ ID NOs: 333 and 334, and    -   (g) SEQ ID NOs: 361 and 362,        wherein the oligonucleotide comprises at least one modified        sugar, a 5′-terminal phosphate group, at least one modified        internucleotide linkage, and at least one modified base.

In other embodiments, the oligonucleotide comprises a sense strand andan antisense strand having a modification pattern according to: SenseStrand:5′-mX-S-mX-mX-mX-mX-mX-mX-fX-fX-fX-fX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-mX-[ademX-GalNAc]-[ademX-GalNAc]-[ademX-GalNAc]-mX-mX-mX-mX-mX-mX-3′hybridized to:

Antisense Strand:5′-[MePhosphonate-4O-mX]-S-fX-S-fX-S-fX-fX-mX-fX-mX-mX-fX-mX-mX-mX-fX-mX-mX-mX-mX-mX-mX-S-mX-S-mX-3′,wherein mX=2′-OMe-modified nucleotide, fX=2-F-modified nucleotide,-S-=phosphorothioate linkage, -=phosphodiester linkage,[MePhosphonate-4O-mX]=4′-O-monomethylphosphonate-2′-O-methyl-modifiednucleotide, and ademX-GalNAc=GalNAc attached to a nucleotide, andwherein the sense stand and the antisense strand comprise nucleotidesequences selected from Table 3, optionally from the group consistingof:

-   -   (a) SEQ ID NOs:139 and 140,    -   (b) SEQ ID NOs:147 and 148,    -   (c) SEQ ID NOs:221 and 222,    -   (d) SEQ ID NOs:273 and 274,    -   (e) SEQ ID NOs:321 and 322,    -   (f) SEQ ID NOs:333 and 334, and    -   (g) SEQ ID NOs:361 and 362.

A. Sugar Modifications: A modified sugar (also referred to herein as asugar analog) includes a modified deoxyribose or ribose moiety in which,for example, one or more modifications occur at the 2′, 3′, 4′, and/or5′ carbon position of the sugar. A modified sugar also includesnon-natural, alternative, carbon structures such as those present inlocked nucleic acids (“LNA”; see, e.g., Koshkin et al. (1998)TETRAHEDRON 54:3607-30), unlocked nucleic acids (“UNA”; see, e.g., Sneadet al. (2013) MOL. THER-NUC. ACIDS 2:e103) and bridged nucleic acids(“BNA”; see, e.g., Imanishi & Obika (2002) CHEM. COMMUN. 16:1653-59).

In some embodiments, the nucleotide modification in the sugar is a2-modification such as, for example, 2′-O-propargyl, 2-O-propylamin,2′-amino, 2′-ethyl, 2′-F, 2′-aminoethyl (EA), 2′-OMe, 2′-MOE,2′-O-[2-(methylamino)-2-oxoethyl] (2′-O-NMA), or 2′-FANA. In certainembodiments, the modification is 2′-F, 2′-OMe, or 2′-MOE. In otherembodiments, the modification in the sugar is a modification of thesugar ring, which includes modification of one or more carbons of thesugar ring. For example, the modification in the sugar is a 2′-oxygen ofthe sugar linked to a 1-carbon or 4′-carbon of the sugar, or a 2′-oxygenlinked to the 1′-carbon or 4′-carbon via an ethylene or methylenebridge. In other embodiments, the modification is an acyclic sugar thatlacks a 2′-carbon to 3′-carbon bond. In other embodiments, themodification is a thiol group such as, for example, in the 4′ positionof the sugar.

The oligonucleotides herein include at least 1 modified nucleotide(e.g., at least 1, at least 5, at least 10, at least 15, at least 20, atleast 25, at least 30, at least 35, at least 40, at least 45, at least50, at least 55, at least 60, or more). In some embodiments, the sensestrand comprises at least 1 modified nucleotide (e.g., at least 1, atleast 5, at least 10, at least 15, at least 20, at least 25, at least30, at least 35, or more). In some embodiments, the antisense strandcomprises at least 1 modified nucleotide (e.g., at least 1, at least 5,at least 10, at least 15, at least 20, or more).

In certain embodiments, all nucleotides of the sense strand except thetetraL are modified. Likewise, all nucleotides of the antisense strandare modified. In some embodiments, all the nucleotides of theoligonucleotide (i.e., paired nucleotides of the sense strand and theantisense strand) are modified. As above, and in some embodiments, themodified nucleotide is a 2-modification (e.g., a 2′-F, 2′-OMe, 2′-MOE,and/or 2′-FANA. In certain embodiments, the modified nucleotide is a2-modification such as, for example, a 2′-F or a 2′-OMe.

In some embodiments, the oligonucleotide comprises a sense strand withabout 10-15%, 10%, 11%, 12%, 13%, 14%, or 15% of the nucleotides of thesense strand comprising a 2′-F modification. In some embodiments, theoligonucleotide comprises a sense strand with about 18-23% (e.g., 18%,19%, 20%, 21%, 22%, or 23%) of the nucleotides of the sense strandcomprising a 2′-F modification. In some embodiments, the oligonucleotidecomprises a sense strand with about 38-43% (e.g., 38%, 39%, 40%, 41%,42%, or 43%) of the nucleotides of the sense strand comprising a 2′-Fmodification. In some embodiments, about 11% of the nucleotides of thesense strand comprise a 2′-F modification. In some embodiments, about22% of the nucleotides of the sense strand comprise a 2′-F modification.In some embodiments, about 40% of the nucleotides of the sense strandcomprise a 2′-F modification. In some embodiments, the oligonucleotidecomprises an antisense strand with about 25% to about 35% (e.g., 25%,26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35%) of the nucleotidesof the antisense strand comprising a 2′-F modification. In someembodiments, about 32% of the nucleotides of the antisense strandcomprise a 2′-F modification. In some embodiments, the oligonucleotidehas about 15% to about 25% (e.g., 15%, 16%, 17%, 18%, 19%, 20%, 21%,22%, 23%, 24%, or 25%) of its nucleotides comprising a 2′-Fmodification. In some embodiments, the oligonucleotide has about 35-45%(e.g., 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44% or 45%) of itsnucleotides comprising a 2′-F modification. In some embodiments, about19% of the nucleotides in the oligonucleotide comprise a 2′-Fmodification. In some embodiments, about 29% of the nucleotides in theoligonucleotide comprise a 2′-F modification. In some embodiments, about40% of the nucleotides in the oligonucleotide comprise a 2′-Fmodification.

Moreover, the oligonucleotides herein can have different modificationpatterns. In some embodiments, the modified oligonucleotide comprise asense strand sequence having a modification pattern as set forth inTable 4 (as well as FIG. 1 ) and an antisense strand having amodification pattern as set forth in Table 4. In some embodiments, oneor more of positions 8, 9, 10, or 11 of the sense strand are modifiedwith a 2′-F. In other embodiments, the sugar moiety at each nucleotideat positions 1 to 7, 12 to 27 and 31 to 36 in the sense strand ismodified with a 2′-OMe. In certain embodiments, positions 8 to 11 of thesense strand are modified with a 2′-F and positions 1 to 7, 12 to 27 and31 to 36 are modified with a 2′-OMe.

In certain additional embodiments, a sense strand comprising a 2′-Fmodified nucleotide at positions 8-11, a 2′-OMe modified nucleotide atpositions 1 to 7, 12 to 27 and 31 to 36, a GalNAc-conjugated nucleotideat position 28, 29 and 30, and a phosphorothioate linkage betweenpositions 1 and 2.

In some embodiments, the antisense strand comprises one or morenucleotides at positions 2-5, 7, 10 and 14 modified with 2′-F, and oneor more nucleotides at positions 1, 6, 8 to 9, 11 to 13 and 15 to 22modified with a 2′-OMe. Certain embodiments disclose an oligonucleotidewith an antisense strand comprising a 2′-F-modified nucleotide atpositions 2 to 5, 7, 10 and 14, and a 2′-OMe-modified nucleotide atpositions 1, 6, 8 to 9, 11 to 13 and 15 to 22.

In certain embodiments, the antisense strand comprises a 2′-F modifiednucleotide at positions 2 to 5, 7, 10 and 14, a 2′-OMe at positions 1,6, 8 to 9, 11 to 13 and 15 to 22, a phosphorothioate linkage betweenpositions 1 and 2, positions 2 and 3, positions 3 and 4, positions 20and 21, and positions 21 and 22.

B. 5′-Terminal Phosphates: 5′-terminal phosphate groups can be used toenhance the interaction of the oligonucleotides herein with Ago2.However, oligonucleotides having a 5′-phosphate group may be susceptibleto degradation via phosphatases or other enzymes, which can limit theirbioavailability in vivo. In some embodiments, the oligonucleotidesherein (e.g., a ds oligonucleotide) comprise analogs of 5′ phosphatesthat are resistant to such degradation. Examples of such phosphateanalogs include, but are not limited to, oxymethyl phosphonate, vinylphosphonate, malonyl phosphonate, or a combination thereof. In certainembodiments the 3′ end of a strand of the oligonucleotides is attachedto a chemical moiety that mimics the electrostatic and steric propertiesof a natural 5′-phosphate group (“phosphate mimic”).

Alternatively, or additionally, the oligonucleotides herein have aphosphate analog at a 4′-carbon position of the sugar (referred to as a“4′-phosphate analog”). See, e.g., Intl. Patent Application PublicationNo. WO 2018/045317. In some embodiments, the oligonucleotides hereininclude a 4′-phosphate analog at a 5′-terminal nucleotide. In someembodiments, the phosphate analog is an oxymethyl phosphonate, in whichthe oxygen atom of the oxymethyl group is bound to the sugar moiety(e.g., at its 4′-carbon) or analog thereof. In other embodiments, the4′-phosphate analog is a thiomethylphosphonate or anaminomethylphosphonate, in which the sulfur atom of the thiomethyl groupor the nitrogen atom of the amino methyl group is bound to the 4′-carbonof the sugar moiety or analog thereof. In certain embodiments, the4′-phosphate analog is an oxymethylphosphonate, which is represented bythe formula —O—CH₂—PO(OH)₂ or —O—CH₂—PO(OR)₂, in which R isindependently selected from H, CH₃, an alkyl group, CH₂CH₂CN,CH₂OCOC(CH₃)₃, CH₂OCH₂CH₂Si (CH₃)₃, or a protecting group. In certainembodiments, the alkyl group is CH₂CH₃. In certain other embodiments, Ris independently selected from H, CH₃, or CH₂CH₃.

C. Modified Internucleotide Linkages: In addition to the abovemodifications, the oligonucleotides herein (e.g., a ds oligonucleotide)comprise a modified internucleotide linkage. In some embodiments,phosphate modifications or substitutions result in oligonucleotides thatcomprise at least about 1 (e.g., at least 1, at least 2, at least 3, orat least 5) modified internucleotide linkages. In some embodiments, theoligonucleotides herein (e.g., a ds oligonucleotide) comprise about 1 toabout 10 (e.g., 1 to 10, 2 to 8, 4 to 6, 3 to 10, 5 to 10, 1 to 5, 1 to3, or 1 to 2) modified internucleotide linkages. In other embodiments,the oligonucleotides comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 modifiedinternucleotide linkages.

Examples of modified internucleotide linkages include, but are notlimited, to, a phosphorodithioate linkage, a phosphorothioate linkage, aphosphotriester linkage, a thionoalkylphosphonate linkage, athionalkylphosphotriester linkage, a phosphoramidite linkage, aphosphonate linkage, or a boranophosphate linkage. In some embodiments,at least one modified internucleotide linkage of any one of theoligonucleotides as disclosed herein is a phosphorothioate linkage.

In some embodiments, the oligonucleotides herein include aphosphorothioate linkage between one or more of positions 1 and 2 of thesense strand, positions 1 and 2 of the antisense strand, positions 2 and3 of the antisense strand, positions 3 and 4 of the antisense strand,positions 20 and 21 of the antisense strand, and positions 21 and 22 ofthe antisense strand. In other embodiments, the oligonucleotidescomprise a phosphorothioate linkage between each of positions 1 and 2 ofthe sense strand, positions 1 and 2 of the antisense strand, positions 2and 3 of the antisense strand, positions 3 and 4 of the antisense strandpositions 20 and 21 of the antisense strand, and positions 21 and 22 ofthe antisense strand.

In certain embodiments, an oligonucleotide herein includes:

-   -   a sense strand having a 2′-F modified nucleotide at positions 8        to 11, a 2′-OMe modified nucleotide at positions 1 to 7, 12 to        27 and 31 to 36, a GalNAc-conjugated nucleotide at position 28,        29 and 30, and a phosphorothioate linkage between positions 1        and 2;    -   an antisense strand having a 2′-F modified nucleotide at        positions 2 to 5, 7, 10 and 14, a 2′-OMe at positions 1, 6, 8 to        9, 11 to 13 and 15 to 22, a phosphorothioate linkage between        positions 1 and 2, positions 2 and 3, positions 3 and 4,        positions 20 and 21, and positions 21 and 22, and a 5′-terminal        nucleotide at position 1 comprising a 4′-phosphate analog,        optionally wherein the 5′-terminal nucleotide comprises        4-O-monomethylphosphonate-2′-O-methyl uridine        [MePhosphonate-4O-mU]; where positions 1 to 20 of the antisense        strand form a duplex region with positions 1 to 20 of the sense        strand, where positions 21 to 36 of the sense strand form a        stem-loop, where positions 27 to 30 form the loop of the        stem-loop, optionally where positions 27 to 30 comprise a        tetraL, where positions 21 and 22 of the antisense strand        comprise an overhang, and where the sense strand and antisense        strands are selected from Table 3, optionally from the group        consisting of:    -   (a) SEQ ID NOs: 139 and 140,    -   (b) SEQ ID NOs: 147 and 148,    -   (c) SEQ ID NOs: 221 and 222,    -   (d) SEQ ID NOs: 273 and 274,    -   (e) SEQ ID NOs: 321 and 322,    -   (f) SEQ ID NOs: 333 and 334, and    -   (g) SEQ ID NOs: 361 and 362.

In certain other embodiments, the modified sense strand and antisensestrands are selected from Table 4, optionally from the group consistingof:

-   -   (a′) SEQ ID NOs: 523 and 524,    -   (b′) SEQ ID NOs: 531 and 532,    -   (c′) SEQ ID NOs:605 and 606,    -   (d′) SEQ ID NOs: 657 and 658,    -   (e′) SEQ ID NOs: 705 and 706,    -   (f′) SEQ ID NOs: 717 and 718, and    -   (g′) SEQ ID NOs: 745 and 746.

D. Base Modifications: In addition to the above modifications, theoligonucleotides herein (e.g., a ds oligonucleotide) also comprise oneor more modified nucleobases. In some embodiments, modified nucleobases(also referred to herein as base analogs) are linked at the 1′ positionof a nucleotide sugar moiety. In some embodiments, the modifiednucleobase is a nitrogenous base. In other embodiments, the modifiednucleobase does not contain nitrogen atom. See, e.g., US PatentApplication Publication No. 2008/0274462. In certain other embodiments,the modified nucleotide is a universal base. However, in certainembodiments, the modified nucleotide does not contain a nucleobase(abasic).

With regard to universal bases, they comprise a heterocyclic moietylocated at the 1′ position of a nucleotide sugar moiety in a modifiednucleotide, or the equivalent position in a nucleotide sugar moietysubstitution, that, when present in a duplex, is positioned oppositemore than one type of base without substantially altering structure ofthe duplex. Moreover, and compared to a reference ss nucleic acid (e.g.,oligonucleotide) that is fully complementary to a target nucleic acid, ass nucleic acid having a universal base forms a duplex with the targetnucleic acid that has a lower T_(m) than a duplex formed with thecomplementary nucleic acid. However, when compared to a reference ssnucleic acid in which the universal base has been replaced with a baseto generate a single mismatch, the ss nucleic acid having the universalbase forms a duplex with the target nucleic acid that has a higher T_(m)than a duplex formed with the nucleic acid having the mismatched base.

Exemplary universal-binding nucleotides include, but are not limited to,inosine, 1-β-D-ribofuranosyl-5-nitroindole and/or1-β-D-ribofuranosyl-3-nitropyrrole (see, e.g., US Patent ApplicationPublication No. 2007/0254362; Van Aerschot et al. (1995) NUCLEIC ACIDSRES. 23:4363-70; Loakes et al. (1995) NUCLEIC ACIDS RES. 23:2361-66; andLoakes & Brown (1994) NUCLEIC ACIDS RES. 22:4039-403).

E. Reversible Modifications: While certain modifications can be made toprotect the oligonucleotides herein (e.g., a ds oligonucleotide such asa RNAi oligonucleotide) from the in vivo environment before reachingtarget cells, they also can be made to reduce the potency or activity ofthe oligonucleotides once they reach the cytosol of the target cell.Reversible modifications therefore can be made such that theoligonucleotide retains desirable properties outside of the cell, whichare then removed upon entering the cytosolic environment of the cell.Reversible modification can be removed, for example, by the action of anintracellular enzyme or by the chemical conditions inside of a cell(e.g., through reduction by intracellular glutathione).

In some embodiments, a reversibly modified nucleotide comprises aglutathione-sensitive moiety. Typically, oligonucleotides are chemicallymodified with cyclic disulfide moieties to mask the negative chargecreated by the internucleotide diphosphate linkages and to improvecellular uptake and nuclease resistance. See, US Patent ApplicationPublication No. 2011/0294869, Intl. Patent Application Publication Nos.WO 2014/088920 and WO 2015/188197, and Meade et al. (2014) NAT.BIOTECHNOL. 32:1256-63. This reversible modification of theinternucleotide diphosphate linkages is designed to be cleavedintracellularly by the reducing environment of the cytosol (e.g.,glutathione). Earlier examples include neutralizing phosphotriestermodifications that are reported to be cleavable inside cells (see, e.g.,Dellinger et al. (2003) J. AM. CHEM. SOC. 125:940-50).

Some reversible modifications protect the oligonucleotide during in vivoadministration (e.g., transit through the blood and/orlysosomal/endosomal compartments of a cell) where the oligonucleotidewill be exposed to nucleases and other harsh environmental conditions(e.g., pH). When released into the cytosol of a cell where the levels ofglutathione are higher compared to extracellular space, the modificationis reversed, and the result is cleaved oligonucleotide. Usingreversible, glutathione-sensitive moieties, it is possible to introducesterically larger chemical groups into the oligonucleotide when comparedto the options available using irreversible chemical modifications. Thisis because these larger chemical groups will be removed in the cytosoland, therefore, should not interfere with the biological activity of theoligonucleotide inside the cytosol of a cell. As a result, these largerchemical groups can be engineered to confer various advantages to theoligonucleotide, such as nuclease resistance, lipophilicity, charge,thermal stability, specificity, and reduced immunogenicity. In someembodiments, the structure of the glutathione-sensitive moiety can beengineered to modify the kinetics of its release.

In some embodiments, the glutathione-sensitive moiety is attached to thesugar of a nucleotide. In certain embodiments, the glutathione-sensitivemoiety is attached to the 2′-carbon of the sugar of a modifiednucleotide. Additionally, or alternatively, the glutathione-sensitivemoiety is attached to the 5′-carbon of a sugar, particularly when themodified nucleotide is the 5′-terminal nucleotide of theoligonucleotide. Additionally, or alternatively, theglutathione-sensitive moiety is attached to the 3′-carbon of sugar,particularly when the modified nucleotide is the 3′-terminal nucleotideof the oligonucleotide. In some embodiments, the glutathione-sensitivemoiety includes a sulfonyl group (see, e.g., Intl. Patent ApplicationPublication No. WO 2018/039364).

VI. Targeting Ligands: It is desirable to target the oligonucleotidesherein (e.g., a ds oligonucleotide such as a RNAi oligonucleotide) toone or more cells or one or more organs. Such a strategy can help toavoid undesirable effects in other organs or to avoid undue loss of theoligonucleotide to cells, tissue, or organs that would not benefittherefrom. Accordingly, the oligonucleotide can be modified tofacilitate targeting and/or delivering to a tissue, cell, or organ(e.g., to facilitate delivering the oligonucleotides to the liver). Insome embodiments, the oligonucleotide is modified to facilitate itsdelivery to the hepatocytes of the liver. In some embodiments, theoligonucleotide comprises at least one nucleotide (e.g., 1, 2, 3, 4, 5,6, or more nucleotides) conjugated to one or more targeting ligand(s).

Exemplary targeting ligands include, but are not limited to, acarbohydrate, amino sugar, cholesterol, peptide, polypeptide, protein,or part of a protein (e.g., an antibody or antibody fragment), or lipid.In some embodiments, the targeting ligand is an aptamer. For example,the targeting ligand is an Arg-Gly-Asp (RGD) peptide for targeting tumorvasculature or glioma cells, Cys-Arg-Glu-Lys-Ala (CREKA) peptide fortargeting tumor vasculature or stoma, transferrin, lactoferrin, or anaptamer for targeting transferrin receptors expressed on central nervoussystem (CNS) vasculature, or an anti-epidermal growth factor receptor(EGFR) antibody for targeting EGFR on glioma cells. In certainembodiments, the targeting ligand is one or more GalNAc moieties.

In some embodiments, 1 or more (e.g., 1, 2, 3, 4, 5, or 6) nucleotidesof the oligonucleotides each can be conjugated to a separate targetingligand. In some embodiments, 2 to 4 nucleotides of the oligonucleotideeach are conjugated to a separate targeting ligand. In otherembodiments, targeting ligands can be conjugated to 2 to 4 nucleotidesat either ends of the sense strand or antisense strand (e.g., targetingligands are conjugated to a 2 to 4 nucleotide overhang or extension onthe 5′ or 3′ end of the sense strand or antisense strand) such that thetargeting ligands resemble bristles of a toothbrush, and theoligonucleotide resembles a toothbrush. For example, the oligonucleotidecomprises a stem-loop at either the 5′ or 3′ end of the sense strand and1, 2, 3, or 4 nucleotides of the L of the stem-loop may be individuallyconjugated to a targeting ligand. In some embodiments, theoligonucleotide comprises a stem-loop at the 3′ end of the sense strand,where the L of the stem-loop includes a triL or a tetraL, and where the3 or 4 nucleotides of the triL or tetraL, respectfully, are individuallyconjugated to a targeting ligand.

GalNAc is a high affinity ligand for the ASGPR, which is primarilyexpressed on the sinusoidal surface of hepatocyte cells and has a majorrole in binding, internalizing, and subsequent clearing circulatingglycoproteins that contain terminal galactose or GalNAc residues(asialoglycoproteins). Conjugation (either indirect or direct) of GalNAcmoieties to the oligonucleotides herein are used to target them to theASGPR expressed on cells. In some embodiments, the oligonucleotides areconjugated to at least one or more GalNAc moieties, where the GalNAcmoieties target the oligonucleotides to an ASGPR expressed on humanliver cells (e.g., human hepatocytes).

The oligonucleotides are conjugated directly or indirectly to amonovalent GalNAc. In some embodiments, the oligonucleotides areconjugated directly or indirectly to more than 1 monovalent GalNAc(i.e., is conjugated to 2, 3, or 4 monovalent GalNAc moieties, and istypically conjugated to 3 or 4 monovalent GalNAc moieties). In someembodiments, the oligonucleotides are conjugated to one or more bivalentGalNAc, trivalent GalNAc, or tetravalent GalNAc moieties.

In some embodiments, 1 or more (e.g., 1, 2, 3, 4, 5, or 6) nucleotidesof the oligonucleotides each can be conjugated to a GalNAc moiety. Insome embodiments, 2 to 4 nucleotides of a L each are conjugated to aseparate GalNAc. In other embodiments, 1 to 3 nucleotides of a triL eachare conjugated to a separate GalNAc. In some embodiments, the targetingligands are conjugated to 2 to 4 nucleotides at either end of the senseor antisense strand (e.g., ligands are conjugated to a 2 to 4 nucleotideoverhang or extension on the 5′ or 3′ end of the sense or antisensestrand) such that the GalNAc moieties resemble bristles of a toothbrush,and the oligonucleotide resembles a toothbrush. In some embodiments, theGalNAc moieties are conjugated to a nucleotide of the sense strand. Forexample, 4 GalNAc moieties are conjugated to nucleotides in the L of thesense strand, where each GalNAc moiety is conjugated to 1 nucleotide. Incertain embodiments, 3 GalNAc moieties are conjugated to nucleotides inthe L of the sense strand, where each GalNAc moiety is conjugated to 1nucleotide.

In some embodiments, the oligonucleotides herein comprise a GalNAcattached to any one or more nucleotides of a triL or tetraL via anylinker described herein, as depicted below (X=heteroatom):

In certain embodiments, the oligonucleotides herein comprise amonovalent GalNAc attached to a guanine nucleotide referred to as2′-aminodiethoxymethanol-Guanine-GalNAc or [ademG-GalNAc], as depictedbelow:

In certain embodiments, the oligonucleotides herein comprise amonovalent GalNAc attached to an adenine nucleotide, referred to as2′-aminodiethoxymethanol-Adenine-GalNAc or [ademA-GalNAc], as depictedbelow:

An example of such conjugation is shown below for a tetraL having from5′ to 3′, the nucleotide sequence GAAA (L—linker, X—heteroatom), wherestem attachment points are shown. Such a tetraL is present, for example,at positions 27-30 of the sense strand listed in Tables 3 and 4, and asshown in FIG. 1 . In the chemical formula,

is used to describe an attachment point to the oligonucleotide strand:

Appropriate methods or chemistry (e.g., click chemistry) are used tolink a targeting ligand to a nucleotide. One way of conjugating thetargeting ligand to a nucleotide is by using a click linker. In someembodiments, an acetal-based linker is used to conjugate the targetingligand to a nucleotide of any one of the oligonucleotides herein.Acetal-based linkers are disclosed, for example, in Intl. PatentApplication Publication No. WO 2016/100401. In some embodiments, thelinker is a labile linker. However, in other embodiments, the linker isstable. An example is shown below for a teraL having from 5′ to 3′, thenucleotides GAAA, in which GalNAc moieties are attached to nucleotidesof the loop using an acetal linker. Such a loop is present, for example,at positions 27-30 of the any one of the sense strands listed in Tables3 or 4. In the chemical formula,

is an attachment point to the oligonucleotide strand:

In some embodiments, a duplex extension (e.g., of up to 3, 4, 5, or 6 bpin length) is provided between the targeting ligand (e.g., a GalNAcmoiety), and the oligonucleotide. In other embodiments, theoligonucleotide does not have a GalNAc conjugated thereto.

Formulations and Pharmaceutical Compositions

The oligonucleotides herein (e.g., a ds oligonucleotide), or apharmaceutically acceptable salt thereof (e.g., trifluroacetate salts,acetate salts or hydrochloride salts), are incorporated into aformulation or pharmaceutical composition. Various formulations havebeen developed to facilitate oligonucleotide use. For example,oligonucleotides can be delivered to an individual or a cellularenvironment using a formulation that minimizes degradation, facilitatesdelivery and/or uptake, or provides another beneficial property to theoligonucleotides in the formulation. In some embodiments, theoligonucleotides are formulated in buffer solutions such as phosphatebuffered saline solutions, liposomes, micellar structures, and capsids.

To improve in vivo compatibility and effectiveness, the oligonucleotidesmay be reacted with any of a number of inorganic and organic acids/basesto form pharmaceutically acceptable acid/base addition salts.Pharmaceutically acceptable salts and common methodologies for preparingthem are well known in the art (see, e.g., Stahl et al., “Handbook ofPharmaceutical Salts: Properties, Selection and Use,” 2^(nd) RevisedEdition (Wiley-VCH, 2011)). Pharmaceutically acceptable salts for useherein include sodium, trifluoroacetate, hydrochloride and acetatesalts.

Formulations of oligonucleotides herein with cationic lipids are used tofacilitate transfection of the oligonucleotides into cells. For example,cationic lipids, such as lipofectin, cationic glycerol derivatives, andpolycationic molecules (e.g., polylysine) can be used. Suitable lipidsinclude Oligofectamine (ThermoFisher Technologies), Lipofectamine (LifeTechnologies), NC388 (Ribozyme Pharmaceuticals, Inc.), or FuGene 6(Roche), all of which are used according to the manufacturer'sinstructions.

Accordingly, in some embodiments, the formulations herein comprise aliposome, a lipid, a lipid complex, a microsphere, a microparticle, ananosphere, or a nanoparticle (such as a lipid nanoparticle) or may beotherwise formulated for administration to the cells, tissues, organs,or body of an individual in need thereof (see, e.g., Remington, “TheScience and Practice of Pharmacy” (L. V. Allen Jr., ed., 22^(nd)Edition, Pharmaceutical Press, 2013).

In some embodiments, the formulations herein further comprise anexcipient, which can confer to a composition improved stability,improved absorption, improved solubility and/or therapeutic enhancementof the active ingredient. In some embodiments, the excipient is abuffering agent (e.g., sodium citrate, sodium phosphate, a tris base, orsodium hydroxide) or a vehicle (e.g., a buffered solution, petrolatum,dimethyl sulfoxide, or mineral oil). In some embodiments, theoligonucleotides herein are lyophilized for extending shelf-life andthen made into a solution before use (e.g., administration to anindividual). Accordingly, the excipient in a pharmaceutical compositionincluding one or more of the oligonucleotides is a lyoprotectant (e.g.,mannitol, lactose, polyethylene glycol, or polyvinylpyrrolidone) or acollapse temperature modifier (e.g., dextran, Ficoll™, or gelatin).

Pharmaceutical compositions are formulated to be compatible with itsintended route of administration. Routes of administration include, butare not limited to, parenteral (e.g., intravenous, intramuscular,intraperitoneal, intradermal, and subcutaneous), oral (e.g.,inhalation), transdermal (e.g., topical), transmucosal, and rectaladministration.

Pharmaceutical compositions suitable for injectable use comprise sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include, but are not limited to, physiological saline,bacteriostatic water, Cremophor EL™ (BASF) or phosphate buffered saline(PBS). The carrier is a solvent or dispersion medium containing, forexample, water, ethanol, polyol (e.g., glycerol, propylene glycol,liquid polyethylene glycol, and the like), as well as suitable mixturesthereof. In many embodiments, it will be preferable to comprise in thecompositions with isotonic agents such as, for example, sugars,polyalcohols such as mannitol, sorbitol and/or sodium chloride. Sterileinjectable solutions are prepared by incorporating the oligonucleotidesherein in a required amount in a selected solvent with one or acombination of ingredients enumerated above, as required, followed byfiltered sterilization.

Moreover, the pharmaceutical compositions comprise at least about 0.1%of a therapeutic agent (e.g., one or more of the oligonucleotidesherein) or more, although the percentage of the therapeutic agent may bebetween about 1% to about 80% or more of the weight or volume of thetotal composition. Factors such as solubility, bioavailability,biological half-life, route of administration, product shelf life, aswell as other pharmacological considerations will be contemplated by oneof skill in the art of preparing such pharmaceutical formulations, andas such, a variety of dosages and treatment regimens may be desirable.

Even though several examples are directed toward liver-targeted deliveryof at least one of the oligonucleotides herein, targeting of othertissues also is contemplated.

Kits

The oligonucleotides herein (e.g., a ds oligonucleotide such as a RNAioligonucleotide) can be incorporated into a kit comprising one or moreof the oligonucleotides herein, and instructions for use. In someembodiments, the kit comprises one or more of the oligonucleotides, anda package insert containing instructions for use of the kit and/or anycomponent thereof. In other embodiments, the kit comprises a suitablecontainer, one or more of the oligonucleotides, one or more controls,and various buffers, reagents, enzymes, and other standard ingredientsas are known in the art.

In some embodiments, the container can be at least one vial, well, testtube, flask, bottle, syringe, or other container means, into which theone or more oligonucleotides are placed, and in some embodiments,suitably aliquoted. In other embodiments, where an additional componentis provided, the kit contains additional containers into which thiscomponent is placed. The kit also comprises a means for containing theone or more oligonucleotides and any other reagent in close confinementfor commercial sale. Such containers include injection or blow-moldedplastic containers into which the desired vials are retained. Containersand/or kits comprise labeling with instructions for use and/or warnings.

In some embodiments, the kit comprises one or more oligonucleotidesherein, and a pharmaceutically acceptable carrier, or a pharmaceuticalcomposition comprising one or more of the oligonucleotides andinstructions for treating or delaying progression of a disease,disorder, or condition associated with SCAP activity in an individual inneed thereof.

Methods

Methods of Making

The oligonucleotides herein (e.g., a ds oligonucleotide such as a RNAioligonucleotide) are made using methods and/or techniques known to oneof skill in the art such as, for example, conventional nucleic acidsolid-phase synthesis. The polynucleotides of the oligonucleotides areassembled on a suitable nucleic acid synthesizer utilizing standardnucleotide or nucleoside precursors (e.g., phosphoramidites). Automatednucleic acid synthesizers, including DNA/RNA synthesizers, arecommercially available from, for example, Applied Biosystems (FosterCity, CA), BioAutomation (Irving, TX), and GE Healthcare Life Sciences(Pittsburgh, PA).

As one of skill in the art understands, other methods and/or techniquesof synthesizing oligonucleotides may be used. Additionally, the varioussynthetic steps are performed in an alternate sequence or order to givethe desired compounds. Other synthetic chemistry transformations,protecting groups (e.g., for hydroxyl, amino, etc. present on thebases), and protecting group methodologies (protection and deprotection)useful in synthesizing the oligonucleotides are known in the art and aredescribed in, for example, Larock, “Comprehensive OrganicTransformations,” VCH Publishers (1989); Greene & Wuts, PROTECTIVEGROUPS IN ORGANIC SYNTHESIS, 2^(nd) Ed., John Wiley & Sons (1991);Fieser & Fieser, FIESER AND FIESER'S REAGENTS FOR ORGANIC SYNTHESIS,John Wiley & Sons (1994); and Paquette, ed., ENCYCLOPEDIA OF REAGENTSFOR ORGANIC SYNTHESIS, John Wiley & Sons (1995).

Methods of Using

I. Methods of Reducing SCAP Activity in Cells, Tissue, Organs, andOrganisms:

The oligonucleotides herein (e.g., a ds oligonucleotide such as RNAioligonucleotides) are used to reduce SCAP mRNA, SCAP protein and/or SCAPactivity in cells, tissues, organs, or individuals. The methods comprisethe steps described herein, and these may be, but not necessarily,carried out in the sequence as described. Other sequences, however, alsoare conceivable. Moreover, individual, or multiple steps are carried outeither in parallel and/or overlapping in time and/or individually or inmultiply repeated steps. Furthermore, the methods comprise additional,unspecified steps.

The methods comprise contacting or delivering to a cell, population ofcells, tissues, organs, or individuals an effective amount any of theoligonucleotides herein for reducing SCAP expression. In someembodiments, reduced SCAP activity is determined by measuring areduction in the amount or level of SCAP mRNA, SCAP protein, and/or SCAPactivity in a cell.

With regard to an appropriate cell type, the cell type is any cell thatexpresses mRNA (e.g., hepatocytes, macrophages, monocyte-derived cells,prostate cancer cells, cells of the brain, endocrine tissue, bonemarrow, lymph nodes, lung, gall bladder, liver, duodenum, smallintestine, pancreas, kidney, gastrointestinal tract, bladder, adiposeand soft tissue, and skin). In some embodiments, the cell is a primarycell obtained from an individual. In some embodiments, the primary cellhas undergone a limited number of passages such that the cellsubstantially maintains is natural phenotypic properties. In someembodiments, the cell is an ex vivo, in vivo, or in vitro cell (i.e.,such that one or more of the oligonucleotides herein can be delivered tothe cell in culture or to an organism in which the cell resides).

In some embodiments, the oligonucleotides herein are delivered to a cellor population of cells using a nucleic acid delivery method known in theart including, but not limited to, injecting a solution containing theoligonucleotides, bombarding by particles covered by theoligonucleotides, exposing the cell or population of cells to a solutioncontaining the oligonucleotides, or electroporating cell membranes inthe presence of the oligonucleotides. Other methods known in the art fordelivering oligonucleotides to cells are used such as, for example,lipid-mediated carrier transport, chemical-mediated transport, andcationic liposome transfection such as calcium phosphate, and others.

Reduced SCAP activity is determined by an assay or technique thatevaluates one or more molecules, properties or characteristics of a cellor population of cells associated with SCAP gene expression (e.g., usinga SCAP expression biomarker) or by an assay or technique that evaluatesmolecules that are directly indicative of SCAP activity in a cell orpopulation of cells (e.g., SCAP mRNA, SCAP protein and/or SCAPactivity). In some embodiments, the extent to which the oligonucleotidesreduce SCAP activity are evaluated by comparing SCAP activity in a cellor population of cells contacted with the oligonucleotides to a controlcell or population of cells (e.g., a cell or population of cells notcontacted with the oligonucleotides or contacted with a controloligonucleotide). In some embodiments, a control amount or level of SCAPactivity in a control cell or population of cells is predetermined, suchthat the control amount or level need not be measured in every instancethe assay or technique is performed. The predetermined level or valuetakes a variety of forms including, but not limited to, a single cut-offvalue, such as a median or mean.

Contacting or delivering the oligonucleotides herein to a cell or apopulation of cells result in reduced SCAP activity. In someembodiments, reduced SCAP activity is relative to a control amount orlevel of SCAP activity in the cell or the population of cells notcontacted with the oligonucleotides or contacted with a controloligonucleotide. In some embodiments, reduced SCAP activity is about 1%or lower, about 5% or lower, about 10% or lower, about 15% or lower,about 20% or lower, about 25% or lower, about 30% or lower, about 35% orlower, about 40% or lower, about 45% or lower, about 50% or lower, about55% or lower, about 60% or lower, about 70% or lower, about 80% orlower, or about 90% or lower relative to a control amount or level ofSCAP activity. In some embodiments, the control amount or level of SCAPactivity is an amount or level of SCAP mRNA, SCAP protein and/or SCAPactivity in the cell or the population of cells that has not beencontacted with oligonucleotides herein. In some embodiments, the effectof delivery of the oligonucleotides to the cell or the population ofcells according to a method herein is assessed after any finite periodor amount of time (e.g., minutes, hours, days, weeks, and/or months).For example, SCAP activity is determined in the cell or the populationof cells at least about 4 hours, about 8 hours, about 12 hours, about 18hours, or about 24 hours. Alternatively, SCAP activity is determined inthe cell or the population of cells at least about 1 day, about 2 days,about 3 days, about 4 days, about 5 days, about 6 days, about 7 days,about 8 days, about 9 days, about 10 days, about 11 days, about 12 days,about 13 days, about 14 days, about 21 days, about 28 days, about 35days, about 42 days, about 49 days, about 56 days, about 63 days, about70 days, about 77 days, or about 84 days or more after contacting ordelivering the oligonucleotides to the cell or population of cells. Inother embodiments, SCAP activity is determined in the cell or thepopulation of cells at least about 1 month, about 2 months, about 3months, about 4 months, about 5 months, or about 6 months or more aftercontacting or delivering the oligonucleotides to the cell or thepopulation of cells.

In some embodiments, the oligonucleotides herein are delivered in theform of a transgene that is engineered to express in a cell one or moreof the oligonucleotides or strands (e.g., sense and antisense strands).For example, the oligonucleotides are delivered using a transgeneengineered to express any oligonucleotide herein. Transgenes may bedelivered using viral vectors (e.g., adenovirus, retrovirus, vacciniavirus, poxvirus, adeno-associated virus, or herpes simplex virus) ornon-viral vectors (e.g., plasmids or synthetic mRNAs). In someembodiments, the transgenes are injected directly to an individual.

II. Methods of Treatment:

Methods of treating an individual having, suspected of having, or atrisk of developing a disease, disorder, or condition associated withSCAP activity comprise administering at least one or more of theoligonucleotides herein (e.g., a ds oligonucleotide such as a RNAioligonucleotide) to the individual. Additionally, methods of treating orattenuating an onset or progression of a disease, disorder, or conditionassociated with SCAP activity in an individual comprise using one ormore of the oligonucleotides herein. Furthermore, methods of achievingone or more therapeutic benefits in an individual having a disease,disorder, or condition associated with SCAP activity comprise providingone or more of the oligonucleotides herein. In some embodiments, theindividual can be treated by administering a therapeutically effectiveamount of any one or more of the oligonucleotides herein. In someembodiments, the treatment comprises reducing SCAP activity. In someembodiments, the individual is treated therapeutically. In someembodiments, the individual is treated prophylactically. In all of theseembodiments, the oligonucleotide of interest is selected from Table 3 or4.

In some embodiments, the one or more oligonucleotides, or apharmaceutical composition including the same, is administered to theindividual having a disease, disorder, or condition associated with SCAPactivity such that SCAP activity is reduced in the individual, therebytreating the individual. In some embodiments, an amount or level of SCAPmRNA is reduced in the individual. In other embodiments, an amount orlevel of SCAP protein is reduced in the individual. In still otherembodiments, an amount or level of SCAP activity is reduced in theindividual. In yet other embodiments, an amount or level of liver TG(e.g., one or more TG(s) or total TGs in liver) and/or cholesterol isreduced in the individual, especially in the liver. In still otherembodiments, an amount or level of liver inflammation can be reduced. Instill other embodiments, an amount of level of liver fibrosis isreduced. In still other embodiments, an amount or level of plasmaaspartate aminotransferase (AST), plasma alanine aminotransferase (ALT),plasma Cytokeratin 18 (CK-18), or even plasma N-terminal type IIIcollagen propeptide (Pro-C3) is reduced. In any of the above disclosedembodiments, the oligonucleotides comprise a sense strand having anucleotide sequence of any one of SEQ ID NOs:532, 531, 605, 657, 705,717 and 745, and an antisense strand having a nucleotide sequence of anyone of SEQ ID NOs:524, 532, 606, 658, 706, 718 and 746.

In some embodiments, SCAP activity is reduced in the individual by atleast about 30%, about 35%, about 40%, about 45%, about 50%, about 55%,about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about90%, about 95%, about 99%, or greater than 99% when compared to SCAPactivity prior to administering the one or more oligonucleotides orpharmaceutical composition thereof. In other embodiments, SCAP activityis reduced in the individual by at least about 30%, about 35%, about40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%,about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, orgreater than 99% when compared to SCAP activity in an individual (e.g.,a reference or control individual) not receiving the one or moreoligonucleotides or pharmaceutical composition or receiving a controloligonucleotide, pharmaceutical composition or treatment.

In certain embodiments, an amount or level of SCAP mRNA is reduced inthe individual by at least about 30%, about 35%, about 40%, about 45%,about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about80%, about 85%, about 90%, about 95%, about 99%, or greater than 99%when compared to an amount or level of SCAP mRNA prior to administeringthe one or more oligonucleotides or pharmaceutical composition thereof.In some embodiments, the amount or level of SCAP mRNA is reduced in theindividual by at least about 30%, about 35%, about 40%, about 45%, about50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,about 85%, about 90%, about 95%, about 99%, or greater than 99% whencompared to an amount or level of SCAP mRNA in an individual (e.g., areference or control individual) not administered the one or moreoligonucleotides or pharmaceutical composition or administered a controloligonucleotide, pharmaceutical composition, or treatment.

In certain embodiments, an amount or level of SCAP protein is reduced inthe individual by at least about 30%, about 35%, about 40%, about 45%,about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about80%, about 85%, about 90%, about 95%, about 99%, or greater than 99%when compared to an amount or level of SCAP protein prior toadministering the one or more oligonucleotides or pharmaceuticalcomposition thereof. In other embodiments, an amount or level of SCAPprotein is reduced in the individual by at least about 30%, about 35%,about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%,or greater than 99% when compared to an amount or level of SCAP proteinin an individual (e.g., a reference or control individual) notadministered the one or more oligonucleotides or pharmaceuticalcomposition or administered a control oligonucleotide, pharmaceuticalcomposition or treatment.

In certain embodiments, an amount or level of SCAP activity is reducedin the individual by at least about 30%, about 35%, about 40%, about45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, about 85%, about 90%, about 95%, about 99%, or greater than99% when compared to an amount or level of SCAP activity prior toadministering the one or more oligonucleotides or pharmaceuticalcomposition thereof. In some embodiments, the amount or level of SCAPactivity is reduced in the individual by at least about 30%, about 35%,about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%,or greater than 99% when compared to an amount or level of SCAP activityin an individual (e.g., a reference or control individual) notadministered the one or more oligonucleotides or pharmaceuticalcomposition or administered a control oligonucleotide, pharmaceuticalcomposition or treatment.

In certain embodiments, an amount or level of TG, especially liver TG,can be reduced in the individual by at least about 30%, about 35%, about40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%,about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, orgreater than 99% when compared to an amount or level of TG prior toadministering the one or more oligonucleotides or pharmaceuticalcomposition thereof. In some embodiments, the amount or level of TG isreduced in the individual by at least about 30%, about 35%, about 40%,about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about75%, about 80%, about 85%, about 90%, about 95%, about 99%, or greaterthan 99% when compared to an amount or level of TG in an individual(e.g., a reference or control individual) not administered the one ormore oligonucleotides or pharmaceutical composition or administered acontrol oligonucleotide, pharmaceutical composition or treatment.

In certain embodiments, an amount or level of cholesterol, especiallyliver cholesterol, can be reduced in the individual by at least about30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%,about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about95%, about 99%, or greater than 99% when compared to an amount or levelof cholesterol prior to administering the one or more oligonucleotidesor pharmaceutical composition thereof. In some embodiments, the amountor level of cholesterol is reduced in the individual by at least about30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%,about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about95%, about 99%, or greater than 99% when compared to an amount or levelof cholesterol in an individual (e.g., a reference or controlindividual) not administered the one or more oligonucleotides orpharmaceutical composition or administered a control oligonucleotide,pharmaceutical composition or treatment.

Here, SCAP activity, the amount or level of SCAP mRNA, SCAP protein,SCAP activity, liver TG, liver cholesterol, or any combination thereof,is reduced in a cell (e.g., a hepatocyte), a population or a group ofcells (e.g., an organoid), a tissue (e.g., liver tissue), a sample(e.g., a liver biopsy sample), an organ (e.g., liver), blood or afraction thereof (e.g., plasma), or any other biological materialobtained or isolated from the individual. In some embodiments, SCAPactivity, the amount or level of SCAP mRNA, SCAP protein, SCAP activity,TG, cholesterol, or any combination thereof, is reduced in more than onetype of cell (e.g., a hepatocyte and one or more other type(s) of cell),more than one groups of cells, more than one type of tissue (e.g., livertissue and one or more other type(s) of tissue), more than one type ofsample (e.g., a liver biopsy sample and one or more other type(s) ofbiopsy sample), more than one organ (e.g., liver and one or more otherorgan(s)), more than one fraction of blood (e.g., plasma and one or moreother blood fraction(s)) obtained or isolated from the individual.

Examples of a disease, disorder, or condition associated with SCAPactivity include, but are not limited to, AH, ALD, CCA, cirrhosis,hepatic fibrosis, hepatic inflammation, HCC, liver steatosis, NAFLD,NASH and PSC, as well as related diseases, disorders, and conditions inan individual such as, for example, hypercholesterolemia,hyperlipidemia, hypertriglyceridemia, ASCVD, diabetes and/or obesity, ora combination thereof.

Because of their high specificity, the oligonucleotides hereinspecifically target mRNAs of target genes of cells, tissues, or organs(e.g., liver). In preventing disease, the target gene is the one that isrequired for initiation or maintenance of the disease or that has beenidentified as being associated with a higher risk of contracting thedisease. In treating disease, one or more of the oligonucleotides hereinare brought into contact with the cells, tissue or organ exhibiting orresponsible for mediating the disease. For example, an oligonucleotidesubstantially complimentary to all or part of a wild-type (i.e., native)or mutated gene associated with a disease, disorder, or conditionassociated with SCAP activity is brought into contact with or introducedinto a cell or tissue type of interest such as a hepatocyte or otherliver cell.

In some embodiments, the target gene is from any mammal, such as ahuman. Any gene may be silenced according to the methods herein.Moreover, the methods herein typically involve administering to anindividual a therapeutically effective amount of one or moreoligonucleotides herein, that is, an amount capable of producing adesirable therapeutic result. The therapeutically acceptable amount isan amount that therapeutically treats a disease or disorder orcondition. The appropriate dosage for any one individual will depend oncertain factors, including the individual's size, body surface area,age, the composition to be administered, the active ingredient(s) in thecomposition, time and route of administration, general health, and othertherapeutic agents being administered concurrently.

In the methods, the individual is administered any one of theoligonucleotides or compositions herein either enterally (e.g., orally,by gastric feeding tube, by duodenal feeding tube, via gastrostomy, orrectally), parenterally (e.g., subcutaneous injection, intravenousinjection or infusion, intra-arterial injection or infusion,intraosseous infusion, intramuscular injection, intracerebral injection,intracerebroventricular injection, or intrathecal), topically (e.g.,epicutaneous, inhalational, via eye drops, or through a mucousmembrane), or by direct injection into a target organ (e.g., the liverof an individual). Typically, the oligonucleotides or compositions areadministered intravenously or subcutaneously.

As a non-limiting set of examples, the oligonucleotides or compositionsherein typically are administered quarterly (once every three months),bi-monthly (once every two months), monthly or weekly. For example, theoligonucleotides or compositions are administered every week or atintervals of two, or three weeks. In certain embodiments, theoligonucleotides, or compositions are administered daily. In someembodiments, an individual is administered one or more loading doses ofthe oligonucleotides or compositions followed by one or more maintenancedoses of the oligonucleotides or compositions.

In some embodiments, the individual is a human, a NHP, or other mammal.In other embodiments, the individual is a domesticated animal such as adog or a cats; livestock such as a horse, cattle, pig, sheep, goat, orchicken; and animals such as a mouse, rat, guinea pig or hamster.

III. Medical Uses: The oligonucleotides herein (e.g., a dsoligonucleotide such as a RNAi oligonucleotide) can be used, or adaptedfor use, to treat an individual (e.g., a human having a disease,disorder, or condition associated with SCAP activity) that would benefitfrom reducing SCAP activity. In some embodiments, the oligonucleotidesare provided for use, or adapted for use, to treat an individual havinga disease, disorder, or condition associated with SCAP activity. Also,the oligonucleotides are provided for use, or adaptable for use, in themanufacture of a medicament or pharmaceutical composition for treating adisease, disorder, or condition associated with SCAP activity. In otherembodiments, the oligonucleotides are provided for use, or adaptable foruse, in targeting SCAP mRNA and reducing SCAP activity (e.g., via theRNAi pathway). In other embodiments, the oligonucleotides are providedfor use, or adaptable for use, in targeting SCAP mRNA and reducing anamount or level of SCAP mRNA, SCAP protein, and/or SCAP activity (i.e.,reducing SCAP activity).

In some embodiments, the methods comprise selecting an individual fortreatment based upon the individual having a marker (e.g., a biomarker)for a disease, disorder, or condition associated with SCAP activity, orsomeone predisposed to the same, such as, but not limited to, SCAP mRNA,SCAP protein, SCAP activity, or a combination thereof. Likewise, and asdetailed below, the methods also comprise additional steps such as, forexample, measuring or obtaining a baseline value for a marker of SCAPactivity (e.g., SCAP protein or other biomarker) and then comparing suchobtained value to one or more other baseline values or values obtainedafter the individual is administered one or more of the oligonucleotidesto assess the effectiveness of treatment.

EXAMPLES

The following non-limiting examples are offered for purposes ofillustration, not limitation.

Synthesis of Oligonucleotides Example 1: Preparing ds RNAiOligonucleotides

Oligonucleotide synthesizing and purifying: ds RNAi oligonucleotides inthe Examples are chemically synthesized using methods described herein.Generally, ds RNAi oligonucleotides are synthesized using solid phaseoligonucleotide synthesis methods as described for 19-23mer siRNAs (see,e.g., Scaringe et al. (1990) NUCLEIC ACIDS RES. 18:5433-41 and Usman etal. (1987) J. AM. CHEM. SOC. 109:7845-45; see also, U.S. Pat. Nos.5,804,683; 5,831,071; 5,998,203; 6,008,400; 6,111,086; 6,117,657;6,353,098; 6,362,323; 6,437,117 and 6,469,158).

Individual RNA strands are synthesized and HPLC purified according tostandard methods (Integrated DNA Technologies). For example, RNAoligonucleotides are synthesized using solid phase phosphoramiditechemistry, deprotected, and desalted on NAP-5 columns (AmershamPharmacia Biotech; Piscataway, NJ) using standard techniques (Damha &Olgivie (1993) METHODS MOL. BIOL. 20:81-114; Wincott et al. (1995)NUCLEIC ACIDS RES. 23:2677-84). The oligomers are purified usingion-exchange high performance liquid chromatography (IE-HPLC) on anAmersham Source 15Q column (1.0 cm×25 cm; Amersham Pharmacia Biotech)using a 15 min step-linear gradient. The gradient varies from 90:10Buffers A:B to 52:48 Buffers A:B, where Buffer A is 100 mM Tris pH 8.5and Buffer B is 100 mM Tris pH 8.5, 1 M NaCl. Samples are monitored at260 nm and peaks corresponding to the full-length oligonucleotidespecies are collected, pooled, desalted on NAP-5 columns, andlyophilized.

The purity of each oligomer is determined by capillary electrophoresis(CE) on a Beckman PACE 5000 (Beckman Coulter, Inc.). The CE capillarieshave a 100 μm inner diameter and contain ssDNA 100R Gel(Beckman-Coulter). Typically, about 0.6 nmole of oligonucleotide isinjected into a capillary, is run in an electric field of 444 V/cm andis detected by UV absorbance at 260 nm. Denaturing Tris-Borate-7 M-urearunning buffer is purchased from Beckman-Coulter. Oligoribonucleotidesare obtained that are at least 90% pure as assessed by CE for use inexperiments described below. Compound identity is verified bymatrix-assisted laser desorption ionization time-of-flight (MALDI-TOF)mass spectroscopy on a Voyager DE™ Biospectometry Work Station (AppliedBiosystems) following the manufacturer's recommended protocol. Relativemolecular masses of all oligomers are obtained, often within 0.2% ofexpected molecular mass.

Preparing duplexes: ss RNA oligomers are resuspended (e.g., at 100 μMconcentration) in duplex buffer having 100 mM potassium acetate, 30 mMHEPES, pH 7.5. Complementary sense and antisense strands are mixed inequal molar amounts to yield a final solution of, for example, 50 μMduplex. Samples are heated to 100° C. for 5 min in RNA buffer (IDT) andare allowed to cool to room temperature before use. The ds RNAoligonucleotides are stored at −20° C. ss RNA oligomers are storedlyophilized or in nuclease-free water at −80° C.

In Vitro Function

Example 2: RNAi Oligonucleotide Modulation of SCAP Activity InVitro—DsiRNA-Based Compounds

SCAP target sequence identifying: To identify RNAi oligonucleotideinhibitors of SCAP expression, a computer-based algorithm is used tocomputationally generate SCAP target sequences suitable for assayingSCAP expression inhibition by the RNAi pathway. The algorithm providesRNAi oligonucleotide antisense strand sequences that are complementaryto suitable SCAP target sequences of human SCAP mRNA (e.g., SEQ IDNO:1). Some of the antisense strand sequences identified by thealgorithm also are complementary to the corresponding SCAP targetsequence of mouse and NHP SCAP mRNA (e.g., SEQ ID NOs: 3 and 7,respectively). From this, 192 ds RNAi oligonucleotides (formatted asDsiRNA oligonucleotides) are generated, each with a unique antisensestrand having a region of complementarity to a SCAP target sequenceidentified by the algorithm.

In vitro cell-based assays: The ability of each of the 192 DsiRNAs toinhibit SCAP expression is determined via in vitro cell-based assays.Further, and as shown herein, the nucleotide sequences for the sensestrand and antisense strand of the DsiRNAs have a distinct pattern ofmodified nucleotides and phosphorothioate linkages. Briefly, Huh7 cellsstably expressing SCAP are transfected with each of the DsiRNAs (1.0 nM)in separate wells of a multi-well cell culture plate. Cells aremaintained for 24 hr following transfection, and then levels ofremaining SCAP mRNA from the transfected cells are determined usingTAQMAN®-based qPCR assays. Two qPCR assays, a 3′ assay and a 5′ assay,are used to determine mRNA levels as measured by HEX probes (e.g., HsHPRT-517-591 and Hs SFRS9-569-712).

The results of the Huh7 cell-based assay with the 192 DsiRNAs are shownin Table 1, where the 192 DsiRNAs have antisense strands that arecomplementary to human, mouse and NHP SCAP mRNA (“triple-common”) orthat are complementary to human and NHP SCAP mRNA (“double-common”).Transfection of DsiRNA that results in less than or equal to 30% SCAPmRNA remaining in the cells when compared to negative controls isconsidered a candidate SCAP expression inhibitor (referred to herein asa “hit”).

TABLE 1 Triple-Common and Double-Common DsiRNA SCAP mRNA Knockdown inHuh7 Cells, 1.0 nM 24 hr-5′ and -3′ Assays % mRNA Remaining (normalizedto Hs HPRT-517 (HEX) and Hs SFRS9-569 (HEX) vs mock control). HPRT-517(HEX) SFRS9-569 (HEX) Average DsiRNA % mRNA % % mRNA % % mRNA % OligoRemaining SEM Remaining SEM Remaining SEM  1* 107.4 21.4 106.0 23.5106.7 1.0  2* 68.9 10.1 52.8 6.2 60.9 11.4  3* 46.4 5.0 39.5 4.7 42.94.9  4* 93.2 8.5 72.0 9.6 82.6 15.0  5* 89.3 14.2 69.2 15.6 79.2 14.2 6* 115.4 17.5 115.4 8.0 115.4 0.0  7* 80.3 6.4 76.4 5.8 78.4 2.8  8*131.0 17.9 126.5 9.7 128.8 3.2  9* 46.8 12.7 42.3 11.1 44.6 3.2  10*55.4 6.7 53.2 5.4 54.3 1.6  11* 150.4 10.7 125.7 9.2 138.1 17.5  12*124.7 34.5 122.0 31.5 123.4 1.9  13* 47.8 9.7 47.8 6.0 47.8 0.0  14*118.5 61.1 132.8 62.8 125.6 10.1  15* 126.7 13.6 125.4 12.5 126.0 0.9 16* 87.3 15.4 91.4 15.7 89.3 2.9  17* 107.4 13.6 105.4 11.8 106.4 1.4 18* 132.1 8.8 133.6 12.2 132.8 1.1  19* 121.1 24.3 109.8 23.5 115.4 8.0 20* 30.5 6.2 36.1 8.3 33.3 3.9  21* 34.4 5.0 42.4 4.4 38.4 5.7  22*59.7 7.7 67.7 6.8 63.7 5.6  23* 106.6 10.5 111.8 9.8 109.2 3.7  24* 10.53.5 9.1 4.4 9.8 1.0  25* 246.5 29.4 152.6 23.9 199.6 66.4  26* 52.0 4.541.1 4.5 46.5 7.7  27* 222.2 49.6 175.3 31.2 198.8 33.2  28* 207.2 57.5156.9 39.5 182.0 35.6  29* 102.7 7.3 96.0 4.8 99.4 4.7  30* 62.1 7.170.3 12.4 66.2 5.8  31* 157.0 25.1 121.6 19.7 139.3 25.0  32* 129.3 59.1131.1 36.6 130.2 1.3  33* 28.1 4.4 24.0 3.4 26.1 2.9  34* 152.3 77.3166.5 76.4 159.4 10.0  35* 129.4 21.7 124.1 16.7 126.7 3.8  36* 90.117.6 89.9 16.3 90.0 0.1  37* 111.7 40.0 111.5 30.2 111.6 0.2  38* 66.911.5 73.6 12.5 70.2 4.7  39* 122.1 24.4 123.0 24.7 122.6 0.6  40* 100.711.1 93.5 15.4 97.1 5.1  41* 54.0 6.9 54.0 7.9 54.0 0.0  42* 29.3 12.839.4 14.5 34.3 7.1  43* 21.0 6.1 18.2 5.5 19.6 1.9  44* 25.5 5.1 29.86.3 27.6 3.0  45* 81.3 39.1 89.7 47.4 85.5 6.0  46* 73.8 23.5 83.3 25.478.5 6.7  47* 89.6 31.0 96.1 37.1 92.9 4.6  48* 86.4 34.3 87.6 37.9 87.00.8 49 40.9 7.0 33.8 5.5 37.3 5.0 50 131.1 15.2 102.5 12.7 116.8 20.2 5162.6 28.3 52.6 24.2 57.6 7.1 52 44.0 4.8 45.3 5.4 44.6 0.9 53 46.5 9.050.6 9.9 48.6 2.9 54 57.5 5.0 58.5 4.8 58.0 0.7 55 58.7 7.7 63.2 10.261.0 3.2 56 74.2 14.3 60.2 13.8 67.2 9.9 57 28.8 4.3 24.5 3.0 26.6 3.058 87.5 9.6 82.0 8.8 84.7 3.9 59 117.5 28.7 123.7 27.6 120.6 4.4 60 59.312.1 51.5 9.5 55.4 5.5 61 40.5 11.0 39.4 8.6 39.9 0.8 62 56.0 26.9 64.029.2 60.0 5.7 63 41.1 6.3 43.3 6.7 42.2 1.5 64 29.9 6.3 39.1 7.3 34.56.5 65 29.4 5.2 28.1 4.6 28.8 0.9 66 29.3 5.6 27.8 5.5 28.6 1.1 67 41.624.9 41.7 22.6 41.6 0.1 68 59.5 8.6 60.2 7.3 59.8 0.5 69 33.4 6.7 37.97.3 35.7 3.2 70 16.0 3.9 17.1 4.3 16.6 0.8 71 111.7 22.9 105.5 21.7108.6 4.4 72 88.8 48.5 45.9 30.6 67.4 30.3 73 34.4 7.9 37.9 8.5 36.2 2.574 129.9 11.4 113.4 11.4 121.6 11.6 75 64.9 7.7 65.3 6.7 65.1 0.3 76187.1 75.1 — — 187.1 75.1 77 218.5 65.1 — — 218.5 65.1 78 98.7 7.9 98.86.7 98.8 0.1 79 31.8 15.2 62.2 18.1 47.0 21.6 80 161.4 27.9 149.7 26.5155.6 8.3 81 68.5 5.4 65.2 3.9 66.9 2.4 82 71.5 4.9 70.0 5.0 70.8 1.0 83111.5 8.3 103.3 6.8 107.4 5.8 84 76.0 4.1 73.1 3.6 74.5 2.1 85 93.6 9.894.7 11.5 94.1 0.7 86 78.3 11.1 83.3 12.0 80.8 3.5 87 100.8 13.4 95.312.6 98.1 3.9 88 114.1 42.1 167.9 40.7 141.0 38.0 89 35.2 3.6 39.7 4.637.4 3.2 90 62.8 7.7 59.1 6.1 61.0 2.6 91 95.4 9.1 76.2 6.8 85.8 13.6 92149.2 11.9 111.5 12.5 130.4 26.7 93 61.1 7.4 54.1 7.5 57.6 5.0 94 78.77.0 82.0 7.2 80.4 2.3 95 67.0 10.3 62.0 9.6 64.5 3.5 96 51.1 5.2 52.14.2 51.6 0.7 97 103.5 16.2 97.9 20.3 100.7 3.9 98 83.0 7.7 81.6 6.1 82.31.0 99 103.2 12.4 98.9 11.6 101.0 3.0 100  90.9 22.9 116.3 28.3 103.618.0 101  44.4 12.9 35.9 9.7 40.1 6.0 102  70.1 7.3 78.0 9.6 74.0 5.5103  41.6 10.9 35.8 11.0 38.7 4.1 104  25.2 7.6 29.7 9.3 27.5 3.2 105 31.5 4.7 33.1 4.8 32.3 1.1 106  20.4 4.3 23.5 4.6 21.9 2.2 107  20.4 1.521.8 2.4 21.1 1.0 108  28.4 6.6 30.6 5.2 29.5 1.5 109  40.1 3.3 42.2 3.741.1 1.5 110  34.9 3.7 35.7 3.8 35.3 0.5 111  89.0 5.5 85.6 6.0 87.3 2.4112  54.3 5.4 54.5 7.7 54.4 0.2 113  30.5 2.0 32.6 2.1 31.6 1.5 114 51.3 3.3 64.5 4.2 57.9 9.3 115  33.9 2.4 36.5 2.6 35.2 1.8 116  86.1 6.694.7 7.1 90.4 6.1 117  29.5 3.8 35.5 2.4 32.5 4.2 118  74.0 8.6 81.1 6.377.6 5.1 119  33.3 2.7 37.5 3.2 35.4 3.0 120  19.3 2.2 20.1 3.0 19.7 0.6121  42.7 8.0 39.7 5.4 41.2 2.1 122  78.4 14.0 70.7 12.2 74.5 5.5 123 34.1 3.6 32.2 4.4 33.1 1.3 124  59.9 7.0 66.0 6.9 62.9 4.3 125  64.1 7.959.2 7.2 61.6 3.4 126  127.6 23.1 148.6 19.6 138.1 14.9 127  152.4 26.3139.9 20.1 146.1 8.8 128  209.1 65.6 150.9 44.7 180.0 41.2 129  91.9 9.278.7 7.3 85.3 9.3 130  91.0 17.5 88.2 20.2 89.6 2.0 131  54.3 5.3 52.73.6 53.5 1.1 132  68.1 6.5 59.3 4.5 63.7 6.2 133  36.1 5.5 33.3 4.2 34.72.0 134  83.3 17.0 73.3 17.0 78.3 7.1 135  68.8 4.9 64.7 4.2 66.8 2.9136  43.4 8.7 48.5 9.2 45.9 3.6 137  61.4 7.4 59.2 5.0 60.3 1.6 138 54.5 6.1 60.9 5.6 57.7 4.6 139  87.3 5.7 83.2 6.4 85.2 2.9 140  89.9 5.490.7 6.0 90.3 0.6 141  57.1 4.7 55.2 3.4 56.2 1.3 142  53.8 5.0 56.3 7.255.1 1.8 143  81.6 8.7 77.9 9.2 79.7 2.6 144  23.6 4.2 22.9 3.1 23.3 0.5145  51.5 16.2 37.3 11.8 44.4 10.1 146  79.5 14.9 66.8 19.5 73.2 9.0147  143.6 14.6 109.5 14.5 126.6 24.1 148  119.3 64.0 74.8 47.1 97.031.4 149  117.9 48.3 65.1 23.6 91.5 37.3 150  224.2 88.9 112.2 58.1168.2 79.2 151  284.8 174.5 162.4 86.4 223.6 86.6 152  82.4 35.3 76.639.1 79.5 4.1 153  54.4 7.8 45.0 9.0 49.7 6.7 154  112.6 20.0 102.3 14.6107.4 7.3 155  115.3 17.1 88.6 10.9 102.0 18.9 156  53.1 6.1 42.5 4.347.8 7.5 157  36.7 5.4 32.7 3.4 34.7 2.9 158  42.9 11.3 41.7 9.6 42.30.9 159  33.2 5.0 34.0 3.6 33.6 0.6 160  113.5 11.4 102.3 9.4 107.9 7.9161  69.4 10.0 70.5 8.1 69.9 0.8 162  58.2 6.6 51.1 6.3 54.6 5.1 163 21.3 3.8 14.8 4.0 18.0 4.6 164  23.1 4.0 17.7 2.9 20.4 3.8 165  13.5 1.79.7 1.7 11.6 2.7 166  29.2 4.6 28.4 4.2 28.8 0.6 167  83.1 7.6 84.0 7.683.5 0.6 168  85.7 25.3 91.5 26.7 88.6 4.1 169  122.6 8.8 91.3 13.8106.9 22.2 170  134.4 11.8 95.4 8.0 114.9 27.6 171  74.5 8.0 52.5 9.263.5 15.6 172  194.8 20.1 158.8 18.1 176.8 25.5 173  168.6 16.7 162.718.0 165.7 4.2 174  37.0 6.5 47.8 9.7 42.4 7.6 175  60.3 40.8 46.6 44.753.4 9.7 176  19.5 2.7 21.0 2.9 20.3 1.1 177  28.7 2.2 23.3 2.4 26.0 3.8178  38.1 3.4 35.8 4.1 36.9 1.7 179  61.3 5.4 55.3 3.4 58.3 4.2 180 152.9 13.8 118.6 10.4 135.8 24.3 181  68.4 7.8 69.5 8.1 68.9 0.8 182 57.6 6.2 58.9 5.8 58.2 0.9 183  127.1 9.9 126.5 10.5 126.8 0.4 184 102.8 11.1 107.8 11.5 105.3 3.6 185  106.6 9.0 94.7 8.2 100.7 8.4 186 54.5 28.0 49.0 25.2 51.8 3.9 187  112.8 9.1 85.6 11.3 99.2 19.2 188 70.6 6.3 72.5 7.3 71.6 1.4 189  50.2 4.5 50.0 5.1 50.1 0.1 190  115.99.8 130.3 9.9 123.1 10.2 191  102.7 13.1 103.6 6.4 103.2 0.6 192  83.318.9 74.9 19.8 79.1 5.9 NOTE: *denotes triple-common.

Additionally, primary human hepatocytes, such as 3D spheroids, aretransfected with each of the DsiRNAs (100 nM) in separate wells of amulti-well cell culture plate. Cells are maintained for 7 days followingtransfection, and then levels of remaining SCAP mRNA from thetransfected cells are determined using TAQMAN®-based qPCR assays. TwoqPCR assays, a 3′ assay and a 5′ assay, are used to determine mRNAlevels as measured by HEX probes (e.g., Hs HPRT-517-591 and HsSFRS9-569-712).

The results of the human hepatocyte 3D spheroid-based assay with theDsiRNAs are shown in Table 2. As above, transfection of a DsiRNA thatresults in less than or equal to 30% SCAP mRNA remaining in the cellswhen compared to negative controls is considered a candidate SCAPexpression inhibitor (referred to herein as a “hit”).

TABLE 2 Triple-Common and Double-Common DsiRNA SCAP mRNA Knockdown in 3DHuman Spheroids, 100 nM 7 days-5′ and -3′ Assays % mRNA Remaining(normalized to Hs HPRT-517 (HEX) and Hs SFRS9-569 (HEX) vs mockcontrol). HPRT-517 (HEX) SFRS9-569 (HEX) Average DsiRNA % mRNA % % mRNA% % mRNA % Oligo Remaining SEM Remaining SEM Remaining SEM  1* 67.3 11.566.3 12.0 66.8 0.7  2* 26.3 12.1 17.7 7.8 22.0 6.1  3* 43.5 4.7 48.0 5.645.7 3.2  4* 64.2 12.4 55.8 13.6 60.0 6.0  5* 73.5 10.2 86.3 11.0 79.99.0  6* 59.8 10.1 94.1 11.3 77.0 24.3  7* 43.9 7.8 60.8 11.1 52.3 11.9 8* 94.4 26.7 110.7 19.3 102.6 11.5  9* 32.7 5.0 53.7 10.3 43.2 14.8 10* 44.1 3.3 61.7 5.1 52.9 12.4  11* 77.1 21.9 97.5 18.5 87.3 14.4  12*64.3 54.4 72.5 53.6 68.4 5.8  13* 6.4 1.9 36.3 6.9 21.4 21.1  14* 80.416.1 104.2 17.8 92.3 16.8  15* 87.1 10.4 111.2 12.5 99.2 17.0  16* 91.319.6 106.5 23.2 98.9 10.8  17* 64.3 6.3 101.3 14.1 82.8 26.2  18* 99.018.7 101.6 28.4 100.3 1.8  19* 75.7 11.1 90.1 16.0 82.9 10.2  20* 35.27.4 45.6 12.1 40.4 7.3  21* 32.7 7.0 35.0 11.0 33.9 1.6  22* 49.3 4.861.6 5.2 55.4 8.7  23* 76.2 16.4 86.0 20.5 81.1 6.9  24* 22.7 4.6 38.07.1 30.4 10.8  25* 110.6 19.0 103.6 19.7 107.1 4.9  26* 57.2 16.0 67.916.1 62.6 7.6  27* 66.4 11.2 78.6 11.9 72.5 8.6  28* 100.0 22.1 134.821.6 117.4 24.6  29* 53.2 13.3 58.1 13.8 55.6 3.5  30* 42.7 10.6 66.515.3 54.6 16.8  31* 46.2 5.8 89.9 12.6 68.0 31.0  32* 59.9 12.1 73.311.8 66.6 9.5  33* 29.4 5.5 38.5 7.4 33.9 6.4  34* 92.3 19.3 127.0 18.3109.7 24.6  35* 95.5 25.6 120.3 27.5 107.9 17.5  36* 69.9 20.9 102.133.2 86.0 22.8  37* 57.1 20.6 82.3 22.0 69.7 17.8  38* 53.7 12.9 70.414.8 62.1 11.8  39* 87.5 19.1 107.1 26.1 97.3 13.8  40* 67.7 16.2 93.726.9 80.7 18.4  41* 78.5 16.1 94.7 14.0 86.6 11.5  42* 43.0 5.8 39.2 5.741.1 2.7  43* 25.8 4.7 29.7 5.4 27.7 2.8  44* 55.4 7.6 72.2 8.6 63.811.9  45* 78.0 7.7 101.9 7.2 89.9 16.9  46* 53.4 38.0 118.6 56.2 86.046.1  47* 69.1 10.8 87.4 13.8 78.2 12.9  48* 155.7 107.9 73.6 57.4 114.758.0 49 57.1 9.2 62.7 11.9 59.9 3.9 50 61.2 6.3 76.6 7.7 68.9 10.9 5137.8 6.3 38.1 7.6 38.0 0.2 52 32.6 5.7 35.9 8.4 34.2 2.3 53 50.4 3.860.5 6.5 55.4 7.1 54 41.8 9.4 51.4 12.0 46.6 6.8 55 58.5 8.0 57.5 11.458.0 0.7 56 82.7 14.0 86.3 17.9 84.5 2.5 57 59.9 5.9 64.3 5.5 62.1 3.158 90.3 11.2 87.7 10.9 89.0 1.9 59 78.7 8.1 83.8 7.3 81.3 3.6 60 40.28.8 35.7 8.0 37.9 3.2 61 46.5 8.6 49.6 8.7 48.1 2.2 62 33.4 6.5 38.3 7.235.9 3.5 63 30.7 5.0 41.2 6.5 36.0 7.4 64 60.0 11.9 48.1 9.6 54.1 8.4 6539.0 5.5 39.0 6.1 39.0 0.1 66 30.3 3.4 25.6 3.6 28.0 3.3 67 14.2 3.617.0 3.7 15.6 1.9 68 33.4 5.2 28.6 5.2 31.0 3.4 69 27.9 1.9 32.7 4.330.3 3.4 70 11.0 1.2 12.4 1.7 11.7 1.0 71 74.5 6.9 87.7 7.5 81.1 9.3 7288.7 7.1 83.0 7.8 85.8 4.1 73 41.3 12.4 46.3 5.4 43.8 3.5 74 77.9 28.799.8 29.7 88.9 15.4 75 45.8 20.7 86.2 21.2 66.0 28.6 76 81.9 13.4 86.915.8 84.4 3.5 77 94.3 14.9 105.8 13.8 100.0 8.2 78 73.6 10.1 84.8 12.679.2 7.9 79 41.2 8.6 47.3 9.2 44.2 4.3 80 68.6 6.7 91.5 8.5 80.0 16.2 8160.5 5.8 67.7 10.2 64.1 5.1 82 49.4 21.3 49.5 12.3 49.5 0.1 83 65.4 7.385.3 10.4 75.4 14.1 84 66.2 10.2 60.9 11.2 63.5 3.8 85 67.7 4.9 78.3 6.673.0 7.5 86 58.2 7.3 71.3 9.5 64.7 9.3 87 66.2 4.9 79.2 8.8 72.7 9.2 8882.1 11.0 94.1 15.9 88.1 8.5 89 83.4 56.0 48.4 20.8 65.9 24.8 90 67.79.7 67.3 9.1 67.5 0.3 91 56.9 23.8 55.5 22.0 56.2 1.0 92 83.5 8.7 84.29.2 83.9 0.4 93 49.2 4.3 45.6 5.4 47.4 2.5 94 62.6 6.2 79.6 9.5 71.1 12.95 43.8 9.1 48.4 10.3 46.1 3.2 96 47.6 6.8 48.7 6.1 48.1 0.7 97 127.0110.9 66.2 54.3 96.6 43.0 98 56.9 5.5 68.5 5.4 62.7 8.2 99 83.0 6.1 84.69.6 83.8 1.1 100  72.1 25.4 137.4 41.3 104.7 46.2 101  39.0 6.9 48.5 9.043.8 6.7 102  55.8 6.4 74.0 10.7 64.9 12.9 103  21.6 10.5 41.7 15.9 31.614.2 104  12.6 7.3 15.9 11.4 14.2 2.3 105  17.6 3.1 60.0 6.8 38.8 30.0106  3.3 0.6 13.9 5.1 8.6 7.5 107  6.4 1.5 22.9 5.2 14.7 11.7 108  17.72.9 44.6 8.3 31.1 19.1 109  15.8 10.0 57.0 30.9 36.4 29.2 110  12.1 1.449.2 5.2 30.6 26.2 111  27.8 6.9 50.5 12.1 39.2 16.1 112  28.8 15.5 64.527.3 46.7 25.2 113  20.7 3.0 40.6 5.4 30.6 14.1 114  37.7 17.1 71.2 22.654.4 23.7 115  17.5 6.2 30.2 11.8 23.9 9.0 116  63.9 9.2 86.9 11.8 75.416.3 117  30.5 2.9 39.4 4.1 34.9 6.3 118  43.9 10.9 61.8 14.2 52.9 12.7119  44.0 5.2 57.4 8.7 50.7 9.5 120  38.1 12.1 55.8 15.3 46.9 12.5 121 59.4 29.3 86.1 35.7 72.8 18.9 122  62.6 12.2 81.9 13.3 72.3 13.7 123 55.7 19.8 85.2 30.5 70.5 20.8 124  35.2 8.0 80.9 21.6 58.1 32.4 125 57.3 8.2 71.1 7.1 64.2 9.7 126  86.3 21.0 88.9 25.2 87.6 1.8 127  83.415.4 106.5 22.9 94.9 16.3 128  119.6 61.8 78.2 59.0 98.9 29.3 129  88.014.9 94.3 16.8 91.2 4.4 130  94.3 68.0 83.8 54.1 89.1 7.5 131  50.2 17.066.4 14.8 58.3 11.5 132  50.9 5.1 47.6 4.6 49.3 2.4 133  33.1 18.1 45.313.4 39.2 8.6 134  38.7 21.1 61.9 25.4 50.3 16.4 135  — — 52.6 31.5 52.631.5 136  34.2 10.0 37.6 10.1 35.9 2.4 137  92.8 24.3 92.7 21.9 92.8 0.1138  49.7 14.6 48.9 11.4 49.3 0.6 139  74.2 11.0 86.8 11.9 80.5 8.9 140 91.6 25.4 92.3 27.1 91.9 0.5 141  61.9 7.5 64.1 8.2 63.0 1.6 142  60.310.8 72.7 17.4 66.5 8.8 143  136.6 56.4 55.2 41.9 95.9 57.6 144  121.242.0 59.0 29.7 90.1 44.0 145  83.5 10.9 87.6 12.3 85.5 2.9 146  73.6 7.367.9 4.9 70.7 4.0 147  104.3 16.4 77.3 8.5 90.8 19.1 148  84.2 12.7 81.010.8 82.6 2.3 149  53.4 9.7 58.5 11.8 55.9 3.6 150  77.3 25.8 69.8 23.973.5 5.4 151  108.2 43.9 120.3 39.8 114.3 8.5 152  66.5 12.1 56.5 11.261.5 7.1 153  43.3 6.4 57.9 11.6 50.6 10.4 154  78.7 8.2 78.4 9.0 78.50.2 155  86.6 8.1 69.9 7.7 78.3 11.8 156  36.0 4.9 40.7 4.3 38.3 3.3157  39.6 3.7 31.2 3.2 35.4 5.9 158  25.2 11.5 26.4 11.8 25.8 0.8 159 24.6 7.4 22.5 6.1 23.6 1.5 160  101.4 17.4 86.1 16.5 93.7 10.8 161  90.312.2 65.3 16.3 77.8 17.7 162  74.4 11.1 66.2 12.6 70.3 5.8 163  19.5 2.810.2 2.2 14.8 6.6 164  23.3 2.6 18.1 3.6 20.7 3.6 165  16.7 7.7 10.4 4.213.6 4.5 166  27.2 4.2 23.2 2.7 25.2 2.8 167  87.0 10.1 77.9 8.7 82.56.4 168  116.7 39.9 89.4 27.8 103.1 19.3 169  100.9 7.7 87.6 5.3 94.29.4 170  95.2 22.4 83.3 18.1 89.3 8.4 171  47.4 10.3 42.2 9.8 44.8 3.7172  63.3 14.3 43.2 10.7 53.2 14.2 173  55.6 10.5 48.9 8.3 52.2 4.7 174 45.5 6.5 38.9 7.5 42.2 4.6 175  45.5 15.1 33.2 13.4 39.4 8.7 176  30.77.3 30.2 6.2 30.4 0.3 177  46.4 7.4 45.0 5.9 45.7 1.0 178  38.9 4.9 41.35.2 40.1 1.7 179  63.6 12.7 49.6 14.6 56.6 9.9 180  80.4 9.9 72.2 8.176.3 5.8 181  68.2 7.5 50.7 7.1 59.4 12.4 182  37.9 22.9 53.0 24.5 45.510.7 183  93.8 20.0 89.0 17.9 91.4 3.4 184  95.3 21.4 132.1 24.0 113.726.0 185  77.4 5.5 79.3 9.4 78.3 1.4 186  55.1 3.5 39.1 4.1 47.1 11.4187  69.3 37.6 78.8 30.9 74.0 6.7 188  81.2 15.0 66.2 14.1 73.7 10.6189  57.2 15.8 58.6 12.4 57.9 1.0 190  69.4 29.6 70.6 28.9 70.0 0.9 191 77.3 8.0 62.2 7.6 69.7 10.7 192  79.9 42.5 67.8 28.7 73.9 8.5 NOTE:*denotes triple-common.

These results show that DsiRNAs designed to target human SCAP mRNA caninhibit SCAP activity in cells (as determined by a reduced amount ofSCAP mRNA in DsiRNA-transfected cells) and that the nucleotide sequencesincluding the DsiRNA hits are useful for generating RNAioligonucleotides to inhibit SCAP activity. Further, these resultsdemonstrate that multiple SCAP target sequences are suitable for theRNAi-mediated inhibition of SCAP activity.

Example 3: RNAi Oligonucleotide Inhibition of SCAP Activity InVitro—GalXC™-Based Compounds

The DsiRNAs screened in Example 2 are selected for evaluation in vitroas GalXC™-based compounds. Briefly, the nucleotide sequences of theDsiRNAs are used to generate corresponding ds RNAi oligonucleotidesincluding a nicked tetraloop GalNAc-conjugated structure (referred toherein as “GalXC™-SCAP oligonucleotides”) having a 36-mer sense strandand a 22-mer antisense strand. Further, the nucleotide sequences for thesense strand and antisense strand of the GalXC™-SCAP oligonucleotideshave a distinct pattern of modified nucleotides and phosphorothioatelinkages (see, e.g., FIG. 1 for a schematic of the generic structure andchemical modification patterns of the GalXC™-SCAP oligonucleotides). Thethree adenosine nucleotides of the tetraloop each are conjugated to aGalNAc moiety (CAS #: 14131-60-3).

TABLE 3 GalXC ™-SCAP Oligonucleotides (unmodified). GalXC- SCAPSense Strand SEQ ID Antisense Strand SEQ ID Oligo (passenger; 36-mer)NO: (guide; 22-mer) NO: 1 UGUUUGCCUACAUC 9 UAAGUAGAUGUAGGCA 10UACUUAGCAGCCGA AACAGG AAGGCUGC 2 GUUUGCCUACAUCU 11 UGAAGUAGAUGUAGGC 12ACUUCAGCAGCCGA AAACGG AAGGCUGC 3 UUUGCCUACAUCUA 13 UAGAAGUAGAUGUAGG 14CUUCUAGCAGCCGA CAAAGG AAGGCUGC 4 GCCUACAUCUACUU 15 UUGGAGAAGUAGAUGU 16CUCCAAGCAGCCGA AGGCGG AAGGCUGC 5 AAGAUCGACAUGGU 17 UACUUGACCAUGUCGA 18CAAGUAGCAGCCGA UCUUGG AAGGCUGC 6 AGAUCGACAUGGUC 19 UGACUUGACCAUGUCG 20AAGUCAGCAGCCGA AUCUGG AAGGCUGC 7 AUCGACAUGGUCAA 21 UUGGACUUGACCAUGU 22GUCCAAGCAGCCGA CGAUGG AAGGCUGC 8 GUGUUGGUGCUCAC 23 UACUUGGUGAGCACCA 24CAAGUAGCAGCCGA ACACGG AAGGCUGC 9 UGUUGGUGCUCACC 25 UGACUUGGUGAGCACC 26AAGUCAGCAGCCGA AACAGG AAGGCUGC 10 GAGAGCUGGUCCAU 27 UUCAUGAUGGACCAGC 28CAUGAAGCAGCCGA UCUCGG AAGGCUGC 11 AGAGCUGGUCCAUC 29 UUUCAUGAUGGACCAG 30AUGAAAGCAGCCGA CUCUGG AAGGCUGC 12 GAGCUGGUCCAUCA 31 UCUUCAUGAUGGACCA 32UGAAGAGCAGCCGA GCUCGG AAGGCUGC 13 AGCUGGUCCAUCAU 33 UUCUUCAUGAUGGACC 34GAAGAAGCAGCCGA AGCUGG AAGGCUGC 14 GCUGGUCCAUCAUG 35 UUUCUUCAUGAUGGAC 36AAGAAAGCAGCCGA CAGCGG AAGGCUGC 15 CUGGUCCAUCAUGA 37 UGUUCUUCAUGAUGGA 38AGAACAGCAGCCGA CCAGGG AAGGCUGC 16 CCGUUGUCUGGAUU 39 UAUGCCAAUCCAGACA 40GGCAUAGCAGCCGA ACGGGG AAGGCUGC 17 UUGUCUGGAUUGGC 41 UAGGAUGCCAAUCCAG 42AUCCUAGCAGCCGA ACAAGG AAGGCUGC 18 UGUCUGGAUUGGCA 43 UCAGGAUGCCAAUCCA 44UCCUGAGCAGCCGA GACAGG AAGGCUGC 19 GUCUGGAUUGGCAU 45 UCCAGGAUGCCAAUCC 46CCUGGAGCAGCCGA AGACGG AAGGCUGC 20 CUGGAUUGGCAUCC 47 UUACCAGGAUGCCAAU 48UGGUAAGCAGCCGA CCAGGG AAGGCUGC 21 UGGAUUGGCAUCCU 49 UAUACCAGGAUGCCAA 50GGUAUAGCAGCCGA UCCAGG AAGGCUGC 22 GGAUUGGCAUCCUG 51 UUAUACCAGGAUGCCA 52GUAUAAGCAGCCGA AUCCGG AAGGCUGC 23 GAUUGGCAUCCUGG 53 UGUAUACCAGGAUGCC 54UAUACAGCAGCCGA AAUCGG AAGGCUGC 24 AUUGGCAUCCUGGU 55 UUGUAUACCAGGAUGC 56AUACAAGCAGCCGA CAAUGG AAGGCUGC 25 CUCCAUCUUCCCAC 57 UAUCAGGUGGGAAGAU 58CUGAUAGCAGCCGA GGAGGG AAGGCUGC 26 CAUCUGCCUGUGGG 59 UUACAUCCCACAGGCA 60AUGUAAGCAGCCGA GAUGGG AAGGCUGC 27 UCUGCCUGUGGGAU 61 UAGUACAUCCCACAGG 62GUACUAGCAGCCGA CAGAGG AAGGCUGC 28 GUGGUGCAAGCUUG 63 UACACCCAAGCUUGCA 64GGUGUAGCAGCCGA CCACGG AAGGCUGC 29 UGGUGCAAGCUUGG 65 UGACACCCAAGCUUGC 66GUGUCAGCAGCCGA ACCAGG AAGGCUGC 30 GGUGCAAGCUUGGG 67 UUGACACCCAAGCUUG 68UGUCAAGCAGCCGA CACCGG AAGGCUGC 31 GUGCAAGCUUGGGU 69 UAUGACACCCAAGCUU 70GUCAUAGCAGCCGA GCACGG AAGGCUGC 32 GCAAGCUUGGGUGU 71 UAGAUGACACCCAAGC 72CAUCUAGCAGCCGA UUGCGG AAGGCUGC 33 CAAGCUUGGGUGUC 73 UGAGAUGACACCCAAG 74AUCUCAGCAGCCGA CUUGGG AAGGCUGC 34 AAGCUUGGGUGUCA 75 UUGAGAUGACACCCAA 76UCUCAAGCAGCCGA GCUUGG AAGGCUGC 35 AGCUUGGGUGUCAU 77 UCUGAGAUGACACCCA 78CUCAGAGCAGCCGA AGCUGG AAGGCUGC 36 GCUUGGGUGUCAUC 79 UUCUGAGAUGACACCC 80UCAGAAGCAGCCGA AAGCGG AAGGCUGC 37 GUGUCUCCUUUUGG 81 UAGGUCCCAAAAGGAG 82GACCUAGCAGCCGA ACACGG AAGGCUGC 38 UGUCUCCUUUUGGG 83 UUAGGUCCCAAAAGGA 84ACCUAAGCAGCCGA GACAGG AAGGCUGC 39 GGGGACCUGUUACA 85 UCUGUCUGUAACAGGU 86GACAGAGCAGCCGA CCCCGG AAGGCUGC 40 GGGACCUGUUACAG 87 UACUGUCUGUAACAGG 88ACAGUAGCAGCCGA UCCCGG AAGGCUGC 41 GGACCUGUUACAGA 89 UGACUGUCUGUAACAG 90CAGUCAGCAGCCGA GUCCGG AAGGCUGC 42 GACCUGUUACAGAC 91 UAGACUGUCUGUAACA 92AGUCUAGCAGCCGA GGUCGG AAGGCUGC 43 ACCUGUUACAGACA 93 UUAGACUGUCUGUAAC 94GUCUAAGCAGCCGA AGGUGG AAGGCUGC 44 UGCCAUUGUCUGCA 95 UAAAGUUGCAGACAAU 96ACUUUAGCAGCCGA GGCAGG AAGGCUGC 45 GCCAUUGUCUGCAA 97 UCAAAGUUGCAGACAA 98CUUUGAGCAGCCGA UGGCGG AAGGCUGC 46 CCAUUGUCUGCAAC 99 UCCAAAGUUGCAGACA 100UUUGGAGCAGCCGA AUGGGG AAGGCUGC 47 AUUGUCUGCAACUU 101 UUGCCAAAGUUGCAGA102 UGGCAAGCAGCCGA CAAUGG AAGGCUGC 48 UCUGCAACUUUGGC 103UUCACUGCCAAAGUUG 104 AGUGAAGCAGCCGA CAGAGG AAGGCUGC 49 CUACCCACUGCUGA105 UGAGUUUCAGCAGUGG 106 AACUCAGCAGCCGA GUAGGG AAGGCUGC 50GCCAGGAACAGGAC 107 UCACAGGUCCUGUUCC 108 CUGUGAGCAGCCGA UGGCGG AAGGCUGC51 GAACAGGACCUGUG 109 UAAUUCCACAGGUCCU 110 GAAUUAGCAGCCGA GUUCGGAAGGCUGC 52 ACAGGACCUGUGGA 111 UUGAAUUCCACAGGUC 112 AUUCAAGCAGCCGACUGUGG AAGGCUGC 53 UGGAAUUCACCACC 113 UACAGGGGUGGUGAAU 114CCUGUAGCAGCCGA UCCAGG AAGGCUGC 54 CUUGUGACCACCUA 115 UUGAUGUAGGUGGUCA116 CAUCAAGCAGCCGA CAAGGG AAGGCUGC 55 UUGUGACCACCUAC 117UAUGAUGUAGGUGGUC 118 AUCAUAGCAGCCGA ACAAGG AAGGCUGC 56 UGUGACCACCUACA119 UGAUGAUGUAGGUGGU 120 UCAUCAGCAGCCGA CACAGG AAGGCUGC 57GUGACCACCUACAU 121 UAGAUGAUGUAGGUGG 122 CAUCUAGCAGCCGA UCACGG AAGGCUGC58 UGACCACCUACAUC 123 UAAGAUGAUGUAGGUG 124 AUCUUAGCAGCCGA GUCAGGAAGGCUGC 59 GACCACCUACAUCA 125 UCAAGAUGAUGUAGGU 126 UCUUGAGCAGCCGAGGUCGG AAGGCUGC 60 ACCACCUACAUCAU 127 UACAAGAUGAUGUAGG 128CUUGUAGCAGCCGA UGGUGG AAGGCUGC 61 CCACCUACAUCAUC 129 UAACAAGAUGAUGUAG130 UUGUUAGCAGCCGA GUGGGG AAGGCUGC 62 CACCUACAUCAUCU 131UAAACAAGAUGAUGUA 132 UGUUUAGCAGCCGA GGUGGG AAGGCUGC 63 ACCUACAUCAUCUU133 UCAAACAAGAUGAUGU 134 GUUUGAGCAGCCGA AGGUGG AAGGCUGC 64CCUACAUCAUCUUG 135 UGCAAACAAGAUGAUG 136 UUUGCAGCAGCCGA UAGGGG AAGGCUGC65 CUACAUCAUCUUGU 137 UGGCAAACAAGAUGAU 138 UUGCCAGCAGCCGA GUAGGGAAGGCUGC 66 ACAUCAUCUUGUUU 139 UUAGGCAAACAAGAUG 140 GCCUAAGCAGCCGAAUGUGG AAGGCUGC 67 AUCAUCUUGUUUGC 141 UUGUAGGCAAACAAGA 142CUACAAGCAGCCGA UGAUGG AAGGCUGC 68 UCAUCUUGUUUGCC 143 UAUGUAGGCAAACAAG144 UACAUAGCAGCCGA AUGAGG AAGGCUGC 69 AUCUUGUUUGCCUA 145UAGAUGUAGGCAAACA 146 CAUCUAGCAGCCGA AGAUGG AAGGCUGC 70 UCUUGUUUGCCUAC147 UUAGAUGUAGGCAAAC 148 AUCUAAGCAGCCGA AAGAGG AAGGCUGC 71UUUCCCCUACCUUG 149 UCACCACAAGGUAGGG 150 UGGUGAGCAGCCGA GAAAGG AAGGCUGC72 UUCCCCUACCUUGU 151 UCCACCACAAGGUAGG 152 GGUGGAGCAGCCGA GGAAGGAAGGCUGC 73 CCCUACCUUGUGGU 153 UUAACCACCACAAGGU 154 GGUUAAGCAGCCGAAGGGGG AAGGCUGC 74 CUACCUUGUGGUGG 155 UAAUAACCACCACAAG 156UUAUUAGCAGCCGA GUAGGG AAGGCUGC 75 UACCUUGUGGUGGU 157 UCAAUAACCACCACAA158 UAUUGAGCAGCCGA GGUAGG AAGGCUGC 76 ACCUUGUGGUGGUU 159UCCAAUAACCACCACA 160 AUUGGAGCAGCCGA AGGUGG AAGGCUGC 77 CCUUGUGGUGGUUA161 UCCCAAUAACCACCACA 162 UUGGGAGCAGCCGA AGGGG AAGGCUGC 78 CUUGUGGUGGUUA163 UACCCAAUAACCACCAC 164 UUGGGUAGCAGCCG AAGGG AAAGGCUGC 79UUGUGGUGGUUAU 165 UAACCCAAUAACCACC 166 UGGGUUAGCAGCCG ACAAGG AAAGGCUGC80 UGUGGUGGUUAUU 167 UUAACCCAAUAACCAC 168 GGGUUAAGCAGCCG CACAGGAAAGGCUGC 81 GUGGUGGUUAUUG 169 UCUAACCCAAUAACCA 170 GGUUAGAGCAGCCGCCACGG AAAGGCUGC 82 UGGUGGUUAUUGG 171 UUCUAACCCAAUAACC 172GUUAGAAGCAGCCG ACCAGG AAAGGCUGC 83 GGUGGUUAUUGGG 173 UCUCUAACCCAAUAAC174 UUAGAGAGCAGCCG CACCGG AAAGGCUGC 84 GUGGUUAUUGGGU 175UUCUCUAACCCAAUAA 176 UAGAGAAGCAGCCG CCACGG AAAGGCUGC 85 UGGUUAUUGGGUU177 UUUCUCUAACCCAAUA 178 AGAGAAAGCAGCCG ACCAGG AAAGGCUGC 86GGUUAUUGGGUUA 179 UAUUCUCUAACCCAAU 180 GAGAAUAGCAGCCG AACCGG AAAGGCUGC87 GUUAUUGGGUUAG 181 UCAUUCUCUAACCCAA 182 AGAAUGAGCAGCCG UAACGGAAAGGCUGC 88 UUAUUGGGUUAGA 183 UACAUUCUCUAACCCA 184 GAAUGUAGCAGCCGAUAAGG AAAGGCUGC 89 AUUGGGUUAGAGA 185 UACACAUUCUCUAACC 186AUGUGUAGCAGCCG CAAUGG AAAGGCUGC 90 UUGGGUUAGAGAA 187 UAACACAUUCUCUAAC188 UGUGUUAGCAGCCG CCAAGG AAAGGCUGC 91 GGUUAGAGAAUGU 189UACCAACACAUUCUCU 190 GUUGGUAGCAGCCG AACCGG AAAGGCUGC 92 GUUAGAGAAUGUG191 UCACCAACACAUUCUC 192 UUGGUGAGCAGCCG UAACGG AAAGGCUGC 93UUAGAGAAUGUGU 193 UGCACCAACACAUUCU 194 UGGUGCAGCAGCCG CUAAGG AAAGGCUGC94 UAGAGAAUGUGUU 195 UAGCACCAACACAUUC 196 GGUGCUAGCAGCCG UCUAGGAAAGGCUGC 95 AGAGAAUGUGUUG 197 UGAGCACCAACACAUU 198 GUGCUCAGCAGCCGCUCUGG AAAGGCUGC 96 GAGAAUGUGUUGG 199 UUGAGCACCAACACAU 200UGCUCAAGCAGCCG UCUCGG AAAGGCUGC 97 AGAAUGUGUUGGU 201 UGUGAGCACCAACACA202 GCUCACAGCAGCCG UUCUGG AAAGGCUGC 98 AAUGUGUUGGUGC 203UUGGUGAGCACCAACA 204 UCACCAAGCAGCCG CAUUGG AAAGGCUGC 99 AUGUGUUGGUGCUC205 UUUGGUGAGCACCAAC 206 ACCAAAGCAGCCGA ACAUGG AAGGCUGC 100UGUGUUGGUGCUCA 207 UCUUGGUGAGCACCAA 208 CCAAGAGCAGCCGA CACAGG AAGGCUGC101 UGGUCCAUCAUGAA 209 UUGUUCUUCAUGAUGG 210 GAACAAGCAGCCGA ACCAGGAAGGCUGC 102 GGUCCAUCAUGAAG 211 UAUGUUCUUCAUGAUG 212 AACAUAGCAGCCGAGACCGG AAGGCUGC 103 CUGACUUCUUCCUU 213 UAUCUGAAGGAAGAAG 214CAGAUAGCAGCCGA UCAGGG AAGGCUGC 104 ACUUCUUCCUUCAG 215 UAGCAUCUGAAGGAAG216 AUGCUAGCAGCCGA AAGUGG AAGGCUGC 105 UCCUUCAGAUGCUG 217UAAAAACAGCAUCUGA 218 UUUUUAGCAGCCGA AGGAGG AAGGCUGC 106 CCUUCAGAUGCUGU219 UGAAAAACAGCAUCUG 220 UUUUCAGCAGCCGA AAGGGG AAGGCUGC 107CUUCAGAUGCUGUU 221 UUGAAAAACAGCAUCU 222 UUUCAAGCAGCCGA GAAGGG AAGGCUGC108 UUCAGAUGCUGUUU 223 UGUGAAAAACAGCAUC 224 UUCACAGCAGCCGA UGAAGGAAGGCUGC 109 CAGAUGCUGUUUUU 225 UUGGUGAAAAACAGCA 226 CACCAAGCAGCCGAUCUGGG AAGGCUGC 110 AGAUGCUGUUUUUC 227 UGUGGUGAAAAACAGC 228ACCACAGCAGCCGA AUCUGG AAGGCUGC 111 GAUGCUGUUUUUCA 229 UAGUGGUGAAAAACAG230 CCACUAGCAGCCGA CAUCGG AAGGCUGC 112 AUGCUGUUUUUCAC 231UCAGUGGUGAAAAACA 232 CACUGAGCAGCCGA GCAUGG AAGGCUGC 113 UGCUGUUUUUCACC233 UACAGUGGUGAAAAAC 234 ACUGUAGCAGCCGA AGCAGG AAGGCUGC 114GCUGUUUUUCACCA 235 UGACAGUGGUGAAAAA 236 CUGUCAGCAGCCGA CAGCGG AAGGCUGC115 UGUUUUUCACCACU 237 UAGGACAGUGGUGAAA 238 GUCCUAGCAGCCGA AACAGGAAGGCUGC 116 GUUUUUCACCACUG 239 UCAGGACAGUGGUGAA 240 UCCUGAGCAGCCGAAAACGG AAGGCUGC 117 UUUUUCACCACUGU 241 UACAGGACAGUGGUGA 242CCUGUAGCAGCCGA AAAAGG AAGGCUGC 118 UUUUCACCACUGUC 243 UGACAGGACAGUGGUG244 CUGUCAGCAGCCGA AAAAGG AAGGCUGC 119 UUCACCACUGUCCU 245UUGGACAGGACAGUGG 246 GUCCAAGCAGCCGA UGAAGG AAGGCUGC 120 CACCACUGUCCUGU247 UAAUGGACAGGACAGU 248 CCAUUAGCAGCCGA GGUGGG AAGGCUGC 121ACCACUGUCCUGUC 249 UCAAUGGACAGGACAG 250 CAUUGAGCAGCCGA UGGUGG AAGGCUGC122 CCACUGUCCUGUCC 251 UUCAAUGGACAGGACA 252 AUUGAAGCAGCCGA GUGGGGAAGGCUGC 123 CACUGUCCUGUCCA 253 UGUCAAUGGACAGGAC 254 UUGACAGCAGCCGAAGUGGG AAGGCUGC 124 ACUGUCCUGUCCAU 255 UUGUCAAUGGACAGGA 256UGACAAGCAGCCGA CAGUGG AAGGCUGC 125 CUAAGCUACCUGAG 257 UUGGUUCUCAGGUAGC258 AACCAAGCAGCCGA UUAGGG AAGGCUGC 126 GAGGUCCAGCAGAG 259UACAACCUCUGCUGGA 260 GUUGUAGCAGCCGA CCUCGG AAGGCUGC 127 GCAGAGGUUGUCCA261 UUGUCAUGGACAACCU 262 UGACAAGCAGCCGA CUGCGG AAGGCUGC 128CAGAGGUUGUCCAU 263 UCUGUCAUGGACAACC 264 GACAGAGCAGCCGA UCUGGG AAGGCUGC129 GAGGAUGAGGAAC 265 UUCCAAAGUUCCUCAU 266 UUUGGAAGCAGCCG CCUCGGAAAGGCUGC 130 GAACUUUGGAGGA 267 UACAAUUUCCUCCAAA 268 AAUUGUAGCAGCCGGUUCGG AAAGGCUGC 131 GACGCUCUUCAGCU 269 UGUAAUAGCUGAAGAG 270AUUACAGCAGCCGA CGUCGG AAGGCUGC 132 ACGCUCUUCAGCUA 271 UUGUAAUAGCUGAAGA272 UUACAAGCAGCCGA GCGUGG AAGGCUGC 133 CGCUCUUCAGCUAU 273UUUGUAAUAGCUGAAG 274 UACAAAGCAGCCGA AGCGGG AAGGCUGC 134 GCUCUUCAGCUAUU275 UGUUGUAAUAGCUGAA 276 ACAACAGCAGCCGA GAGCGG AAGGCUGC 135CUCUUCAGCUAUUA 277 UUGUUGUAAUAGCUGA 278 CAACAAGCAGCCGA AGAGGG AAGGCUGC136 UCUUCAGCUAUUAC 279 UAUGUUGUAAUAGCUG 280 AACAUAGCAGCCGA AAGAGGAAGGCUGC 137 CUUCAGCUAUUACA 281 UGAUGUUGUAAUAGCU 282 ACAUCAGCAGCCGAGAAGGG AAGGCUGC 138 UUCAGCUAUUACAA 283 UUGAUGUUGUAAUAGC 284CAUCAAGCAGCCGA UGAAGG AAGGCUGC 139 CCAGCCUGACCUCA 285 UGCAGGUGAGGUCAGG286 CCUGCAGCAGCCGA CUGGGG AAGGCUGC 140 CAGCCUGACCUCAC 287UAGCAGGUGAGGUCAG 288 CUGCUAGCAGCCGA GCUGGG AAGGCUGC 141 AGCCUGACCUCACC289 UAAGCAGGUGAGGUCA 290 UGCUUAGCAGCCGA GGCUGG AAGGCUGC 142GCCUGACCUCACCU 291 UUAAGCAGGUGAGGUC 292 GCUUAAGCAGCCGA AGGCGG AAGGCUGC143 CCUGACCUCACCUG 293 UUUAAGCAGGUGAGGU 294 CUUAAAGCAGCCGA CAGGGGAAGGCUGC 144 CUGACCUCACCUGC 295 UAUUAAGCAGGUGAGG 296 UUAAUAGCAGCCGAUCAGGG AAGGCUGC 145 UGACCUCACCUGCU 297 UAAUUAAGCAGGUGAG 298UAAUUAGCAGCCGA GUCAGG AAGGCUGC 146 GACCUCACCUGCUU 299 UCAAUUAAGCAGGUGA300 AAUUGAGCAGCCGA GGUCGG AAGGCUGC 147 ACCUCACCUGCUUA 301UUCAAUUAAGCAGGUG 302 AUUGAAGCAGCCGA AGGUGG AAGGCUGC 148 CCUCACCUGCUUAA303 UGUCAAUUAAGCAGGU 304 UUGACAGCAGCCGA GAGGGG AAGGCUGC 149CUCACCUGCUUAAU 305 UUGUCAAUUAAGCAGG 306 UGACAAGCAGCCGA UGAGGG AAGGCUGC150 UCACCUGCUUAAUU 307 UGUGUCAAUUAAGCAG 308 GACACAGCAGCCGA GUGAGGAAGGCUGC 151 CACCUGCUUAAUUG 309 UGGUGUCAAUUAAGCA 310 ACACCAGCAGCCGAGGUGGG AAGGCUGC 152 ACCUGCUUAAUUGA 311 UUGGUGUCAAUUAAGC 312CACCAAGCAGCCGA AGGUGG AAGGCUGC 153 CCUGCUUAAUUGAC 313 UUUGGUGUCAAUUAAG314 ACCAAAGCAGCCGA CAGGGG AAGGCUGC 154 CUGCUUAAUUGACA 315UGUUGGUGUCAAUUAA 316 CCAACAGCAGCCGA GCAGGG AAGGCUGC 155 UGCUUAAUUGACAC317 UAGUUGGUGUCAAUUA 318 CAACUAGCAGCCGA AGCAGG AAGGCUGC 156GCUUAAUUGACACC 319 UAAGUUGGUGUCAAUU 320 AACUUAGCAGCCGA AAGCGG AAGGCUGC157 CUUAAUUGACACCA 321 UAAAGUUGGUGUCAAU 322 ACUUUAGCAGCCGA UAAGGGAAGGCUGC 158 UUAAUUGACACCAA 323 UAAAAGUUGGUGUCAA 324 CUUUUAGCAGCCGAUUAAGG AAGGCUGC 159 UAAUUGACACCAAC 325 UGAAAAGUUGGUGUCA 326UUUUCAGCAGCCGA AUUAGG AAGGCUGC 160 AUUGAAGGGGUGC 327 UAGCACAGCACCCCUUC328 UGUGCUAGCAGCCG AAUGG AAAGGCUGC 161 CUUGGACAAAAGGA 329UCACAAUCCUUUUGUC 330 UUGUGAGCAGCCGA CAAGGG AAGGCUGC 162 UUGGACAAAAGGA331 UCCACAAUCCUUUUGU 332 UUGUGGAGCAGCCG CCAAGG AAAGGCUGC 163UCAACGGUUCCCUU 333 UAAAUCAAGGGAACCG 334 GAUUUAGCAGCCGA UUGAGG AAGGCUGC164 CAACGGUUCCCUUG 335 UGAAAUCAAGGGAACC 336 AUUUCAGCAGCCGA GUUGGGAAGGCUGC 165 AACGGUUCCCUUGA 337 UAGAAAUCAAGGGAAC 338 UUUCUAGCAGCCGACGUUGG AAGGCUGC 166 ACGGUUCCCUUGAU 339 UAAGAAAUCAAGGGAA 340UUCUUAGCAGCCGA CCGUGG AAGGCUGC 167 GUACAUUGACCAGA 341 UCAUGGUCUGGUCAAU342 CCAUGAGCAGCCGA GUACGG AAGGCUGC 168 ACCUGUACCACCUC 343UCACAGGAGGUGGUAC 344 CUGUGAGCAGCCGA AGGUGG AAGGCUGC 169 CCUGUACCACCUCC345 UACACAGGAGGUGGUA 346 UGUGUAGCAGCCGA CAGGGG AAGGCUGC 170GUACCACCUCCUGU 347 UAUGACACAGGAGGUG 348 GUCAUAGCAGCCGA GUACGG AAGGCUGC171 GCACAGGCAUCAAG 349 UUAGAACUUGAUGCCU 350 UUCUAAGCAGCCGA GUGCGGAAGGCUGC 172 ACAGGCAUCAAGUU 351 UAGUAGAACUUGAUGC 352 CUACUAGCAGCCGACUGUGG AAGGCUGC 173 CAGGCAUCAAGUUC 353 UGAGUAGAACUUGAUG 354UACUCAGCAGCCGA CCUGGG AAGGCUGC 174 AGGCAUCAAGUUCU 355 UGGAGUAGAACUUGAU356 ACUCCAGCAGCCGA GCCUGG AAGGCUGC 175 GGCAUCAAGUUCUA 357UUGGAGUAGAACUUGA 358 CUCCAAGCAGCCGA UGCCGG AAGGCUGC 176 GCAUCAAGUUCUAC359 UAUGGAGUAGAACUUG 360 UCCAUAGCAGCCGA AUGCGG AAGGCUGC 177CAUCAAGUUCUACU 361 UAAUGGAGUAGAACUU 362 CCAUUAGCAGCCGA GAUGGG AAGGCUGC178 AUCAAGUUCUACUC 363 UGAAUGGAGUAGAACU 364 CAUUCAGCAGCCGA UGAUGGAAGGCUGC 179 UCAAGUUCUACUCC 365 UUGAAUGGAGUAGAAC 366 AUUCAAGCAGCCGAUUGAGG AAGGCUGC 180 CAAGUUCUACUCCA 367 UCUGAAUGGAGUAGAA 368UUCAGAGCAGCCGA CUUGGG AAGGCUGC 181 AAGUUCUACUCCAU 369 UGCUGAAUGGAGUAGA370 UCAGCAGCAGCCGA ACUUGG AAGGCUGC 182 AGUUCUACUCCAUU 371UUGCUGAAUGGAGUAG 372 CAGCAAGCAGCCGA AACUGG AAGGCUGC 183 GUUCUACUCCAUUC373 UCUGCUGAAUGGAGUA 374 AGCAGAGCAGCCGA GAACGG AAGGCUGC 184GUGUCAUCUCAGAC 375 UAGGUUGUCUGAGAUG 376 AACCUAGCAGCCGA ACACGG AAGGCUGC185 CAUCUCAGACAACC 377 UCAGCAGGUUGUCUGA 378 UGCUGAGCAGCCGA GAUGGGAAGGCUGC 186 UCAGACAACCUGCU 379 UUCACCAGCAGGUUGU 380 GGUGAAGCAGCCGACUGAGG AAGGCUGC 187 CGGGGACCUGUUAC 381 UUGUCUGUAACAGGUC 382AGACAAGCAGCCGA CCCGGG AAGGCUGC 188 GACAACGCUGCCAU 383 UAGACAAUGGCAGCGU384 UGUCUAGCAGCCGA UGUCGG AAGGCUGC 189 GCUGCCUCCUGACU 385UAUUACAGUCAGGAGG 386 GUAAUAGCAGCCGA CAGCGG AAGGCUGC 190 CUGCCUCCUGACUG387 UUAUUACAGUCAGGAG 388 UAAUAAGCAGCCGA GCAGGG AAGGCUGC 191UAAUAUUAAACUU 389 UUUAAAAAAGUUUAAU 390 UUUUAAAGCAGCCG AUUAGG AAAGGCUGC192 AAUAUUAAACUUU 391 UUUUAAAAAAGUUUAA 392 UUUAAAAGCAGCCG UAUUGGAAAGGCUGC

TABLE 4 GalXC ™-SCAP Oligonucleotides (modified). GalXC- SCAP SenseStrand SEQ Antisense Strand SEQ Oligo (passenger; 36-mer) ID NO: (guide;22-mer) ID NO: 1 [mUs][mG][mU][mU] 393 [MePhosphonate-4O- 394[mU][mG][mC][fC][fU] mUs][fAs][fAs][fG][fU] [fA]]fC][mA][mU][mC][mA][fG][mA][mU][fG][mU] [mU][mA][mC][mU][mU] [mA][mG][fG][mC][mA][mA][mA][mG][mC][mA][mG] [mA][mC][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 2[mGs][mU][mU][mU] 395 [MePhosphonate-4O- 396 [mG][mC][mC][fU][fA]mUs][fGs][fAs][fA][fG][mU] [fC][fA][mU][mC][mU] [fA][mG][mA][fU][mG][mU][mA][mC][mU][mU][mC] [mA][fG][mG][mC][mA][mA] [mA][mG][mC][mA][mG][mA][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 3[mUs][mU][mU][mG] 397 [MePhosphonate-4O- 398 [mC][mC][mU][fA][fC]mUs][fAs][fGs][fA][fA][mG] [fA][fU][mC][mU][mA] [fU][mA][mG][fA][mU][mG][mC][mU][mU][mC][mU] [mU][fA][mG][mG][mC][mA] [mA][mG][mC][mA][mG][mA][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 4[mGs][mC][mC][mU] 399 [MePhosphonate-4O- 400 [mA][mC][mA][fU][fC]mUs][fUs][fGs][fG][fA][mG] [fU][fA][mC][mU][mU] [fA][mA][mG][fU][mA][mG][mC][mU][mC][mC][mA] [mA][fU][mG][mU][mA][mG] [mA][mG][mC][mA][mG][mG][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 5[mAs][mA][mG][mA] 401 [MePhosphonate-4O- 402 [mU][mC][mG][fA][fC]mUs][fAs][fCs][fU][fU][mG] [fA][fU][mG][mG][mU] [fA][mC][mC][fA][mU][mG][mC][mA][mA][mG][mU] [mU][fC][mG][mA][mU][mC] [mA][mG][mC][mA][mG][mU][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 6[mAs][mG][mA][mU] 403 [MePhosphonate-4O- 404 [mC][mG][mA][fC][fA]mUs][fGs][fAs][fC][fU][mU] [fU][fG][mG][mU][mC] [fG][mA][mC][fC][mA][mU][mA][mA][mG][mU][mC] [mG][fU][mC][mG][mA][mU] [mA][mG][mC][mA][mG][mC][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 7[mAs][mU][mC][mG] 405 [MePhosphonate-4O- 406 [mA][mC][mA][fU][fG]mUs][fUs][fGs][fG][fA][mC] [fG][fU][mC][mA][mA] [fU][mU][mG][fA][mC][mC][mG][mU][mC][mC][mA] [mA][fU][mG][mU][mC][mG] [mA][mG][mC][mA][mG][mA][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 8[mGs][mU][mG][mU] 407 [MePhosphonate-4O- 408 [mU][mG][mG][fU][fG]mUs][fAs][fCs][fU][fU][mG] [fC][fU][mC][mA][mC] [fG][mU][mG][fA][mG][mC][mC][mA][mA][mG][mU] [mA][fC][mC][mA][mA][mC] [mA][mG][mC][mA][mG][mA][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 9[mUs][mG][mU][mU] 409 [MePhosphonate-4O- 410 [mG][mG][mU][fG][fC]mUs][fGs][fAs][fC][fU][mU] [fU][fC][mA][mC][mC] [fG][mG][mU][fG][mA][mG][mA][mA][mG][mU][mC] [mC][fA][mC][mC][mA][mA] [mA][mG][mC][mA][mG][mC][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 10[mGs][mA][mG][mA] 411 [MePhosphonate-4O- 412 [mG][mC][mU][fG][fG]mUs][fUs][fCs][fA][fU][mG] [fU][fC][mC][mA][mU] [fA][mU][mG][fG][mA][mC][mC][mA][mU][mG][mA] [mC][fA][mG][mC][mU][mC] [mA][mG][mC][mA][mG][mU][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 11[mAs][mG][mA][mG] 413 [MePhosphonate-4O- 414 [mC][mU][mG][fG][fU]mUs][fUs][fUs][fC][fA][mU] [fC][fC][mA][mU][mC] [fG][mA][mU][fG][mG][mA][mA][mU][mG][mA][mA] [mC][fC][mA][mG][mC][mU] [mA][mG][mC][mA][mG][mC][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 12[mGs][mA][mG][mC] 415 [MePhosphonate-4O- 416 [mU][mG][mG][fU][fC]mUs][fCs][fUs][fU][fC][mA] [fC][fA][mU][mC][mA] [fU][mG][mA][fU][mG][mG][mU][mG][mA][mA][mG] [mA][fC][mC][mA][mG][mC] [mA][mG][mC][mA][mG][mU][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 13[mAs][mG][mC][mU] 417 [MePhosphonate-4O- 418 [mG][mG][mU][fC][fC]mUs][fUs][fCs][fU][fU][mC] [fA][fU][mC][mA][mU] [fA][mU][mG][fA][mU][mG][mG][mA][mA][mG][mA] [mG][fA][mC][mC][mA][mG] [mA][mG][mC][mA][mG][mC][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 14[mGs][mC][mU][mG] 419 [MePhosphonate-4O- 420 [mG][mU][mC][fC][fA]mUs][fUs][fUs][fC][fU][mU] [fU][fC][mA][mU][mG] [fC][mA][mU][fG][mA][mU][mA][mA][mG][mA][mA] [mG][fG][mA][mC][mC][mA] [mA][mG][mC][mA][mG][mG][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 15[mCs][mU][mG][mG] 421 [MePhosphonate-4O- 422 [mU][mC][mC][fA][fU]mUs][fGs][fUs][fU][fC][mU] [fC][fA][mU][mG][mA] [fU][mC][mA][fU][mG][mA][mA][mG][mA][mA][mC] [mU][fG][mG][mA][mC][mC] [mA][mG][mC][mA][mG][mA][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 16[mCs][mC][mG][mU] 423 [MePhosphonate-4O- 424 [mU][mG][mU][fC][fU]mUs][fAs][fUs][fG][fC][mC] [fG][fG][mA][mU][mU] [fA][mA][mU][fC][mC][mA][mG][mG][mC][mA][mU] [mG][fA][mC][mA][mA][mC] [mA][mG][mC][mA][mG][mG][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 17[mUs][mU][mG][mU] 425 [MePhosphonate-4O- 426 [mC][mU][mG][fG][fA]mUs][fAs][fGs][fG][fA][mU] [fU][fU][mG][mG][mC] [fG][mC][mC][fA][mA][mU][mA][mU][mC][mC][mU] [mC][fC][mA][mG][mA][mC] [mA][mG][mC][mA][mG][mA][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 18[mUs][mG][mU][mC] 427 [MePhosphonate-4O- 428 [mU][mG][mG][fA][fU]mUs][fCs][fAs][fG][fG][mA] [fU][fG][mG][mC][mA] [fU][mG][mC][fC][mA][mA][mU][mC][mC][mU][mG] [mU][fC][mC][mA][mG][mA] [mA][mG][mC][mA][mG][mC][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 19[mGs][mU][mC][mU] 429 [MePhosphonate-4O- 430 [mG][mG][mA][fU][fU]mUs][fCs][fCs][fA][fG][mG] [fG][fG][mC][mA][mU] [fA][mU][mG][fC][mC][mA][mC][mC][mU][mG][mG] [mA][fU][mC][mC][mA][mG] [mA][mG][mC][mA][mG][mA][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 20[mCs][mU][mG][mG] 431 [MePhosphonate-4O- 432 [mA][mU][mU][fG][fG]mUs][fUs][fAs][fC][fC][mA] [fC][fA][mU][mC][mC] [fG][mG][mA][fU][mG][mC][mU][mG][mG][mU][mA] [mC][fA][mA][mU][mC][mC] [mA][mG][mC][mA][mG][mA][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 21[mUs][mG][mG][mA] 433 [MePhosphonate-4O- 434 [mU][mU][mG][fG][fC]mUs][fAs][fUs][fA][fC][mC] [fA][fU][mC][mC][mU] [fA][mG][mG][fA][mU][mG][mG][mG][mU][mA][mU] [mC][fC][mA][mA][mU][mC] [mA][mG][mC][mA][mG][mC][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 22[mGs][mG][mA][mU] 435 [MePhosphonate-4O- 436 [mU][mG][mG][fC][fA]mUs][fUs][fAs][fU][fA][mC] [fU][fC][mC][mU][mG] [fC][mA][mG][fG][mA][mU][mG][mU][mA][mU][mA] [mG][fC][mC][mA][mA][mU] [mA][mG][mC][mA][mG][mC][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 23[mGs][mA][mU][mU] 437 [MePhosphonate-4O- 438 [mG][mG][mC][fA][fU]mUs][fGs][fUs][fA][fU][mA] [fC][fC][mU][mG][mG] [fC][mC][mA][fG][mG][mA][mU][mA][mU][mA][mC] [mU][fG][mC][mC][mA][mA] [mA][mG][mC][mA][mG][mU][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 24[mAs][mU][mU][mG] 439 [MePhosphonate-4O- 440 [mG][mC][mA][fU][fC]mUs][fUs][fGs][fU][fA][mU] [fC][fU][mG][mG][mU] [fA][mC][mC][fA][mG][mG][mA][mU][mA][mC][mA] [mA][fU][mG][mC][mC][mA] [mA][mG][mC][mA][mG][mA][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 25[mCs][mU][mC][mC] 441 [MePhosphonate-4O- 442 [mA][mU][mC][fU][fU]mUs][fAs][fUs][fC][fA][mG] [fC][fC][mC][mA][mC] [fG][mU][mG][fG][mG][mA][mC][mU][mG][mA][mU] [mA][fG][mA][mU][mG][mG] [mA][mG][mC][mA][mG][mA][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 26[mCs][mA][mU][mC] 443 [MePhosphonate-4O- 444 [mU][mG][mC][fC][fU]mUs][fUs][fAs][fC][fA][mU] [fG][fU][mG][mG][mG] [fC][mC][mC][fA][mC][mA][mA][mU][mG][mU][mA] [mG][fG][mC][mA][mG][mA] [mA][mG][mC][mA][mG][mU][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 27[mUs][mC][mU][mG] 445 [MePhosphonate-4O- 446 [mC][mC][mU][fG][fU]mUs][fAs][fGs][fU][fA][mC] [fG][fG][mG][mA][mU] [fA][mU][mC][fC][mC][mA][mG][mU][mA][mC][mU] [mC][fA][mG][mG][mC][mA] [mA][mG][mC][mA][mG][mG][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 28[mGs][mU][mG][mG] 447 [MePhosphonate-4O- 448 [mU][mG][mC][fA][fA]mUs][fAs][fCs][fA][fC][mC] [fG][fC][mU][mU][mG] [fC][mA][mA][fG][mC][mU][mG][mG][mU][mG][mU] [mU][fG][mC][mA][mC][mC] [mA][mG][mC][mA][mG][mA][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 29[mUs][mG][mG][mU] 449 [MePhosphonate-4O- 450 [mG][mC][mA][fA][fG]mUs][fGs][fAs][fC][fA][mC] [fC][fU][mU][mG][mG] [fC][mC][mA][fA][mG][mC][mG][mU][mG][mU][mC] [mU][fU][mG][mC][mA][mC] [mA][mG][mC][mA][mG][mC][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 30[mGs][mG][mU][mG] 451 [MePhosphonate-4O- 452 [mC][mA][mA][fG][fC]mUs][fUs][fGs][fA][fC][mA] [fU][fU][mG][mG][mG] [fC][mC][mC][fA][mA][mG][mU][mG][mU][mC][mA] [mC][fU][mU][mG][mC][mA] [mA][mG][mC][mA][mG][mC][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 31[mGs][mU][mG][mC] 453 [MePhosphonate-4O- 454 [mA][mA][mG][fC][fU]mUs][fAs][fUs][fG][fA][mC] [fU][fG][mG][mG][mU] [fA][mC][mC][fC][mA][mA][mG][mU][mC][mA][mU] [mG][fC][mU][mU][mG][mC] [mA][mG][mC][mA][mG][mA][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 32[mGs][mC][mA][mA] 455 [MePhosphonate-4O- 456 [mG][mC][mU][fU][fG]mUs][fAs][fGs][fA][fU][mG] [fG][fG][mU][mG][mU] [fA][mC][mA][fC][mC][mC][mC][mA][mU][mC][mU] [mA][fA][mG][mC][mU][mU] [mA][mG][mC][mA][mG][mG][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 33[mCs][mA][mA][mG] 457 [MePhosphonate-4O- 458 [mC][mU][mU][fG][fG]mUs][fGs][fAs][fG][fA][mU] [fG][fU][mG][mU][mC] [fG][mA][mC][fA][mC][mC][mA][mU][mC][mU][mC] [mC][fA][mA][mG][mC][mU] [mA][mG][mC][mA][mG][mU][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 34[mAs][mA][mG][mC] 459 [MePhosphonate-4O- 460 [mU][mU][mG][fG][fG]mUs][fUs][fGs][fA][fG][mA] [fU][fG][mU][mC][mA] [fU][mG][mA][fC][mA][mC][mU][mC][mU][mC][mA] [mC][fC][mA][mA][mG][mC] [mA][mG][mC][mA][mG][mU][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 35[mAs][mG][mC][mU] 461 [MePhosphonate-4O- 462 [mU][mG][mG][fG][fU]mUs][fCs][fUs][fG][fA][mG] [fG][fU][mC][mA][mU] [fA][mU][mG][fA][mC][mA][mC][mU][mC][mA][mG] [mC][fC][mC][mA][mA][mG] [mA][mG][mC][mA][mG][mC][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 36[mGs][mC][mU][mU] 463 [MePhosphonate-4O- 464 [mG][mG][mG][fU][fG]mUs][fUs][fCs][fU][fG][mA] [fU][fC][mA][mU][mC] [fG][mA][mU][fG][mA][mC][mU][mC][mA][mG][mA] [mA][fC][mC][mC][mA][mA] [mA][mG][mC][mA][mG][mG][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 37[mGs][mU][mG][mU] 465 [MePhosphonate-4O- 466 [mC][mU][mC][fC][fU]mUs][fAs][fGs][fG][fU][mC] [fU][fU][mU][mG][mG] [fC][mC][mA][fA][mA][mA][mG][mA][mC][mC][mU] [mG][fG][mA][mG][mA][mC] [mA][mG][mC][mA][mG][mA][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 38[mUs][mG][mU][mC] 467 [MePhosphonate-4O- 468 [mU][mC][mC][fU][fU]mUs][fUs][fAs][fG][fG][mU] [fU][fU][mG][mG][mG] [fC][mC][mC][fA][mA][mA][mA][mC][mC][mU][mA] [mA][fG][mG][mA][mG][mA] [mA][mG][mC][mA][mG][mC][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 39[mGs][mG][mG][mG] 469 [MePhosphonate-4O- 470 [mA][mC][mC][fU][fG]mUs][fCs][fUs][fG][fU][mC] [fU][fU][mA][mC][mA] [fU][mG][mU][fA][mA][mC][mG][mA][mC][mA][mG] [mA][fG][mG][mU][mC][mC] [mA][mG][mC][mA][mG][mC][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 40[mGs][mG][mG][mA] 471 [MePhosphonate-4O- 472 [mC][mC][mU][fG][fU]mUs][fAs][fCs][fU][fG][mU] [fU][fA][mC][mA][mG] [fC][mU][mG][fU][mA][mA][mA][mC][mA][mG][mU] [mC][fA][mG][mG][mU][mC] [mA][mG][mC][mA][mG][mC][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GaINAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 41[mGs][mG][mA][mC] 473 [MePhosphonate-4O- 474 [mC][mU][mG][fU][fU]mUs][fGs][fAs][fC][fU][mG] [fA][fC][mA][mG][mA] [fU][mC][mU][fG][mU][mA][mC][mA][mG][mU][mC] [mA][fC][mA][mG][mG][mU] [mA][mG][mC][mA][mG][mC][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 42[mGs][mA][mC][mC] 475 [MePhosphonate-4O- 476 [mU][mG][mU][fU][fA]mUs][fAs][fGs][fA][fC][mU] [fC][fA][mG][mA][mC] [fG][mU][mC][fU][mG][mU][mA][mG][mU][mC][mU] [mA][fA][mC][mA][mG][mG] [mA][mG][mC][mA][mG][mU][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 43[mAs][mC][mC][mU] 477 [MePhosphonate-4O- 478 [mG][mU][mU][fA][fC]mUs][fUs][fAs][fG][fA][mC] [fA][fG][mA][mC][mA] [fU][mG][mU][fC][mU][mG][mG][mU][mC][mU][mA] [mU][fA][mA][mC][mA][mG] [mA][mG][mC][mA][mG][mG][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 44[mUs][mG][mC][mC] 479 [MePhosphonate-4O- 480 [mA][mU][mU][fG][fU]mUs][fAs][fAs][fA][fG][mU] [fC][fU][mG][mC][mA] [fU][mG][mC][fA][mG][mA][mA][mC][mU][mU][mU] [mC][fA][mA][mU][mG][mG] [mA][mG][mC][mA][mG][mC][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 45[mGs][mC][mC][mA] 481 [MePhosphonate-4O- 482 [mU][mU][mG][fU][fC]mUs][fCs][fAs][fA][fA][mG] [fU][fG][mC][mA][mA] [fU][mU][mG][fC][mA][mG][mC][mU][mU][mU][mG] [mA][fC][mA][mA][mU][mG] [mA][mG][mC][mA][mG][mG][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 46[mCs][mC][mA][mU] 483 [MePhosphonate-4O- 484 [mU][mG][mU][fC][fU]mUs][fCs][fCs][fA][fA][mA] [fG][fC][mA][mA][mC] [fG][mU][mU][fG][mC][mA][mU][mU][mU][mG][mG] [mG][fA][mC][mA][mA][mU] [mA][mG][mC][mA][mG][mG][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 47[mAs][mU][mU][mG] 485 [MePhosphonate-4O- 486 [mU][mC][mU][fG][fC]mUs][fUs][fGs][fC][fC][mA] [fA][fA][mC][mU][mU] [fA][mA][mG][fU][mU][mG][mU][mG][mG][mC][mA] [mC][fA][mG][mA][mC][mA] [mA][mG][mC][mA][mG][mA][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 48[mUs][mC][mU][mG] 487 [MePhosphonate-4O- 488 [mC][mA][mA][fC][fU]mUs][fUs][fCs][fA][fC][mU] [fU][fU][mG][mG][mC] [fG][mC][mC][fA][mA][mA][mA][mG][mU][mG][mA] [mG][fU][mU][mG][mC][mA] [mA][mG][mC][mA][mG][mG][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 49[mCs][mU][mA][mC] 489 [MePhosphonate-4O- 490 [mC][mC][mA][fC][fU]mUs][fGs][fAs][fG][fU][mU] [fG][fC][mU][mG][mA] [fU][mC][mA][fG][mC][mA][mA][mA][mC][mU][mC] [mG][fU][mG][mG][mG][mU] [mA][mG][mC][mA][mG][mA][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 50[mGs][mC][mC][mA] 491 [MePhosphonate-4O- 492 [mG][mG][mA][fA][fC]mUs][fCs][fAs][fC][fA][mG] [fA][fG][mG][mA][mC] [fG][mU][mC][fC][mU][mG][mC][mU][mG][mU][mG] [mU][fU][mC][mC][mU][mG] [mA][mG][mC][mA][mG][mG][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 51[mGs][mA][mA][mC] 493 [MePhosphonate-4O- 494 [mA][mG][mG][fA][fC]mUs][fAs][fAs][fU][fU][mC] [fC][fU][mG][mU][mG] [fC][mA][mC][fA][mG][mG][mG][mA][mA][mU][mU] [mU][fC][mC][mU][mG][mU] [mA][mG][mC][mA][mG][mU][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 52[mAs][mC][mA][mG] 495 [MePhosphonate-4O- 496 [mG][mA][mC][fC][fU]mUs][fUs][fGs][fA][fA][mU] [fG][fU][mG][mG][mA] [fU][mC][mC][fA][mC][mA][mA][mU][mU][mC][mA] [mG][fG][mU][mC][mC][mU] [mA][mG][mC][mA][mG][mG][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 53[mUs][mG][mG][mA] 497 [MePhosphonate-4O- 498 [mA][mU][mU][fC][fA]mUs][fAs][fCs][fA][fG][mG] [fC][fC][mA][mC][mC] [fG][mG][mU][fG][mG][mU][mC][mC][mU][mG][mU] [mG][fA][mA][mU][mU][mC] [mA][mG][mC][mA][mG][mC][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 54[mCs][mU][mU][mG] 499 [MePhosphonate-4O- 500 [mU][mG][mA][fC][fC]mUs][fUs][fGs][fA][fU][mG] [fA][fC][mC][mU][mA] [fU][mA][mG][fG][mU][mG][mC][mA][mU][mC][mA] [mG][fU][mC][mA][mC][mA] [mA][mG][mC][mA][mG][mA][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 55[mUs][mU][mG][mU] 501 [MePhosphonate-4O- 502 [mG][mA][mC][fC][fA]mUs][fAs] [fUs][fG][fA][mU] [fC][fC][mU][mA][mC][fG][mU][mA][fG][mG][mU] [mA][mU][mC][mA][mU] [mG][fG][mU][mC][mA][mC][mA][mG][mC][mA][mG] [mA][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 56[mUs][mG][mU][mG] 503 [MePhosphonate-4O- 504 [mA][mC][mC][fA][fC]mUs][fGs][fAs][fU][fG][mA] [fC][fU][mA][mC][mA] [fU][mG][mU][fA][mG][mG][mU][mC][mA][mU][mC] [mU][fG][mG][mU][mC][mA] [mA][mG][mC][mA][mG][mC][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 57[mGs][mU][mG][mA] 505 [MePhosphonate-4O- 506 [mC][mC][mA][fC][fC]mUs][fAs][fGs][fA][fU][mG] [fU][fA][mC][mA][mU] [fA][mU][mG][fU][mA][mG][mC][mA][mU][mC][mU] [mG][fU][mG][mG][mU][mC] [mA][mG][mC][mA][mG][mA][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 58[mUs][mG][mA][mC] 507 [MePhosphonate-4O- 508 [mC][mA][mC][fC][fU]mUs][fAs][fAs][fG][fA][mU] [fA][fC][mA][mU][mC] [fG][mA][mU][fG][mU][mA][mA][mU][mC][mU][mU] [mG][fG][mU][mG][mG][mU] [mA][mG][mC][mA][mG][mC][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 59[mGs][mA][mC][mC] 509 [MePhosphonate-4O- 510 [mA][mC][mC][fU][fA]mUs][fCs][fAs][fA][fG][mA] [fC][fA][mU][mC][mA] [fU][mG][mA][fU][mG][mU][mU][mC][mU][mU][mG] [mA][fG][mG][mU][mG][mG] [mA][mG][mC][mA][mG][mU][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 60[mAs][mC][mC][mA] 511 [MePhosphonate-4O- 512 [mC][mC][mU][fA][fC]mUs][fAs][fCs][fA][fA][mG] [fA][fU][mC][mA][mU] [fA][mU][mG][fA][mU][mG][mC][mU][mU][mG][mU] [mU][fA][mG][mG][mU][mG] [mA][mG][mC][mA][mG][mG][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 61[mCs][mC][mA][mC] 513 [MePhosphonate-4O- 514 [mC][mU][mA][fC][fA]mUs][fAs][fAs][fC][fA][mA] [fU][fC][mA][mU][mC] [fG][mA][mU][fG][mA][mU][mU][mU][mG][mU][mU] [mG][fU][mA][mG][mG][mU] [mA][mG][mC][mA][mG][mG][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 62[mCs][mA][mC][mC] 515 [MePhosphonate-4O- 516 [mU][mA][mC][fA][fU]mUs][fAs][fAs][fA][fC][mA] [fC][fA][mU][mC][mU] [fA][mG][mA][fU][mG][mA][mU][mG][mU][mU][mU] [mU][fG][mU][mA][mG][mG] [mA][mG][mC][mA][mG][mU][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 63[mAs][mC][mC][mU] 517 [MePhosphonate-4O- 518 [mA][mC][mA][fU][fC]mUs][fCs][fAs][fA][fA][mC] [fA][fU][mC][mU][mU] [fA][mA][mG][fA][mU][mG][mG][mU][mU][mU][mG] [mA][fU][mG][mu][mA][mG] [mA][mG][mC][mA][mG][mG][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 64[mCs][mC][mU][mA] 519 [MePhosphonate-4O- 520 [mC][mA][mU][fC][fA]mUs][fGs][fCs][fA][fA][mA] [fU][fC][mU][mU][mG] [fC][mA][mA][fG][mA][mU][mU][mU][mU][mG][mC] [mG][fA][mU][mG][mU][mA] [mA][mG][mC][mA][mG][mG][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 65[mCs][mU][mA][mC] 521 [MePhosphonate-4O- 522 [mA][mU][mC][fA][fU]mUs][fGs][fGs][fC][fA][mA] [fC][fU][mU][mG][mU] [fA][mC][mA][fA][mG][mA][mU][mU][mG][mC][mC] [mU][fG][mA][mU][mG][mU] [mA][mG][mC][mA][mG][mA][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 66[mAs][mC][mA][mU] 523 [MePhosphonate-4O- 524 [mC][mA][mU][fC][fU]mUs][fUs][fAs][fG][fG][mC] [fU][fG][mU][mU][mU] [fA][mA][mA][fC][mA][mA][mG][mC][mC][mU][mA] [mG][fA][mU][mG][mA][mU] [mA][mG][mC][mA][mG][mG][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 67[mAs][mU][mC][mA] 525 [MePhosphonate-4O- 526 [mU][mC][mU][fU][fG]mUs][fUs][fGs][fU][fA][mG] [fU][fU][mU][mG][mC] [fG][mC][mA][fA][mA][mC][mC][mU][mA][mC][mA] [mA][fA][mG][mA][mU][mG] [mA][mG][mC][mA][mG][mA][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 68[mUs][mC][mA][mU] 527 [MePhosphonate-4O- 528 [mC][mU][mU][fG][fU]mUs][fAs][fUs][fG][fU][mA] [fU][fU][mG][mC][mC] [fG][mG][mC][fA][mA][mA][mU][mA][mC][mA][mU] [mC][fA][mA][mG][mA][mU] [mA][mG][mC][mA][mG][mG][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 69[mAs][mU][mC][mU] 529 [MePhosphonate-4O- 530 [mU][mG][mU][fU][fU]mUs][fAs][fGs][fA][fU][mG] [fG][fC][mC][mU][mA] [fU][mA][mG][fG][mC][mA][mC][mA][mU][mC][mU] [mA][fA][mC][mA][mA][mG] [mA][mG][mC][mA][mG][mA][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 70[mUs][mC][mU][mU] 531 [MePhosphonate-4O- 532 [mG][mU][mU][fU][fG]mUs][fUs][fAs][fG][fA][mU] [fC][fC][mU][mA][mC] [fG][mU][mA][fG][mG][mC][mA][mU][mC][mU][mA] [mA][fA][mA][mC][mA][mA] [mA][mG][mC][mA][mG][mG][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 71[mUs][mU][mU][mC] 533 [MePhosphonate-4O- 534 [mC][mC][mC][fU][fA]mUs][fCs][fAs][fC][fC][mA] [fC][fC][mU][mU][mG] [fC][mA][mA][fG][mG][mU][mU][mG][mG][mU][mG] [mA][fG][mG][mG][mG][mA] [mA][mG][mC][mA][mG][mA][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 72[mUs][mU][mC][mC] 535 [MePhosphonate-4O- 536 [mC][mC][mU][fA][fC]mUs][fCs][fCs][fA][fC][mC] [fC][fU][mU][mG][mU] [fA][mC][mA][fA][mG][mG][mG][mG][mU][mG][mG] [mU][fA][mG][mG][mG][mG] [mA][mG][mC][mA][mG][mA][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 73[mCs][mC][mC][mU] 537 [MePhosphonate-4O- 538 [mA][mC][mC][fU][fU]mUs][fUs][fAs][fA][fC][mC] [fG][fU][mG][mG][mU] [fA][mC][mC][fA][mC][mA][mG][mG][mU][mU][mA] [mA][fG][mG][mU][mA][mG] [mA][mG][mC][mA][mG][mG][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 74[mCs][mU][mA][mC] 539 [MePhosphonate-4O- 540 [mC][mU][mU][fG][fU]mUs][fAs][fAs][fU][fA][mA] [fG][fG][mU][mG][mG] [fC][mC][mA][fC][mC][mA][mU][mU][mA][mU][mU] [mC][fA][mA][mG][mG][mU] [mA][mG][mC][mA][mG][mA][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 75[mUs][mA][mC][mC] 541 [MePhosphonate-4O- 542 [mU][mU][mG][fU][fG]mUs][fCs][fAs][fA][fU][mA] [fG][fU][mG][mG][mU] [fA][mC][mC][fA][mC][mC][mU][mA][mU][mU][mG] [mA][fC][mA][mA][mG][mG] [mA][mG][mC][mA][mG][mU][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 76[mAs][mC][mC][mU] 543 [MePhosphonate-4O- 544 [mU][mG][mU][fG][fG]mUs][fCs][fCs][fA][fA][mU] [fU][fG][mG][mU][mU] [fA][mA][mC][fC][mA][mC][mA][mU][mU][mG][mG] [mC][fA][mC][mA][mA][mG] [mA][mG][mC][mA][mG][mG][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 77[mCs][mC][mU][mU] 545 [MePhosphonate-4O- 546 [mG][mU][mG][fG][fU]mUs][fCs][fCs][fC][fA][mA] [fG][fG][mU][mU][mA] [fU][mA][mA][fC][mC][mA][mU][mU][mG][mG][mG] [mC][fC][mA][mC][mA][mA] [mA][mG][mC][mA][mG][mG][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 78[mCs][mU][mU][mG] 547 [MePhosphonate-4O- 548 [mU][mG][mG][fU][fG]mUs][fAs][fCs][fC][fC][mA] [fG][fU][mU][mA][mU] [fA][mU][mA][fA][mC][mC][mU][mG][mG][mG][mU] [mA][fC][mC][mA][mC][mA] [mA][mG][mC][mA][mG][mA][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 79[mUs][mU][mG][mU] 549 [MePhosphonate-4O- 550 [mG][mG][mU][fG][fG]mUs][fAs][fAs][fC][fC][mC] [fU][fU][mA][mU][mU] [fA][mA][mU][fA][mA][mC][mG][mG][mG][mU][mU] [mC][fA][mC][mC][mA][mC] [mA][mG][mC][mA][mG][mA][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 80[mUs][mG][mU][mG] 551 [MePhosphonate-4O- 552 [mG][mU][mG][fG][fU]mUs][fUs][fAs][fA][fC][mC] [fU][fA][mU][mU][mG] [fC][mA][mA][fU][mA][mA][mG][mG][mU][mU][mA] [mC][fC][mA][mC][mC][mA] [mA][mG][mC][mA][mG][mC][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 81[mGs][mU][mG][mG] 553 [MePhosphonate-4O- 554 [mU][mG][mG][fU][fU]mUs][fCs][fUs][fA][fA][mC] [fA][fU][mU][mG][mG] [fC][mC][mA][fA][mU][mA][mG][mU][mU][mA][mG] [mA][fC][mC][mA][mC][mC] [mA][mG][mC][mA][mG][mA][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 82[mUs][mG][mG][mU] 555 [MePhosphonate-4O- 556 [mG][mG][mU][fU][fA]mUs][fUs][fCs][fU][fA][mA] [fU][fU][mG][mG][mG] [fC][mC][mC][fA][mA][mU][mU][mU][mA][mG][mA] [mA][fA][mC][mC][mA][mC] [mA][mG][mC][mA][mG][mC][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 83[mGs][mG][mU][mG] 557 [MePhosphonate-4O- 558 [mG][mU][mU][fA][fU]mUs][fCs][fUs][fC][fU][mA] [fU][fG][mG][mG][mU] [fA][mC][mC][fC][mA][mA][mU][mA][mG][mA][mG] [mU][fA][mA][mC][mC][mA] [mA][mG][mC][mA][mG][mC][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 84[mGs][mU][mG][mG] 559 [MePhosphonate-4O- 560 [mU][mU][mA][fU][fU]mUs][fUs][fCs][fU][fC][mU] [fG][fG][mG][mU][mU] [fA][mA][mC][fC][mC][mA][mA][mG][mA][mG][mA] [mA][fU][mA][mA][mC][mC] [mA][mG][mC][mA][mG][mA][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 85[mUs][mG][mG][mU] 561 [MePhosphonate-4O- 562 [mU][mA][mU][fU][fG]mUs][fUs][fUs][fC][fU][mC] [fG][fG][mU][mU][mA] [fU][mA][mA][fC][mC][mC][mG][mA][mG][mA][mA] [mA][fA][mU][mA][mA][mC] [mA][mG][mC][mA][mG][mC][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 86[mGs][mG][mU][mU] 563 [MePhosphonate-4O- 564 [mA][mU][mU][fG][fG]mUs][fAs][fUs][fU][fC][mU] [fG][fU][mU][mA][mG] [fC][mU][mA][fA][mC][mC][mA][mG][mA][mA][mU] [mC][fA][mA][mU][mA][mA] [mA][mG][mC][mA][mG][mC][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 87[mGs][mU][mU][mA] 565 [MePhosphonate-4O- 566 [mU][mU][mG][fG][fG]mUs][fCs][fAs][fU][fU][mC] [fU][fU][mA][mG][mA] [fU][mC][mU][fA][mA][mC][mG][mA][mA][mU][mG] [mC][fC][mA][mA][mU][mA] [mA][mG][mC][mA][mG][mA][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 88[mUs][mU][mA][mU] 567 [MePhosphonate-4O- 568 [mU][mG][mG][fG][fU]mUs][fAs][fCs][fA][fU][mU] [fU][fA][mG][mA][mG] [fC][mU][mC][fU][mA][mA][mA][mA][mU][mG][mU] [mC][fC][mC][mA][mA][mU] [mA][mG][mC][mA][mG][mA][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 89[mAs][mU][mU][mG] 569 [MePhosphonate-4O- 570 [mG][mG][mU][fU][fA]mUs][fAs][fCs][fA][fC][mA] [fG][fA][mG][mA][mA] [fU][mU][mC][fU][mC][mU][mU][mG][mU][mG][mU] [mA][fA][mC][mC][mC][mA] [mA][mG][mC][mA][mG][mA][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 90[mUs][mU][mG][mG] 571 [MePhosphonate-4O- 572 [mG][mU][mU][fA][fG]mUs][fAs][fAs][fC][fA][mC] [fA][fG][mA][mA][mU] [fA][mU][mU][fC][mU][mC][mG][mU][mG][mU][mU] [mU][fA][mA][mC][mC][mC] [mA][mG][mC][mA][mG][mA][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 91[mGs][mG][mU][mU] 573 [MePhosphonate-4O- 574 [mA][mG][mA][fG][fA]mUs][fAs][fCs][fC][fA][mA] [fA][fU][mG][mU][mG] [fC][mA][mC][fA][mU][mU][mU][mU][mG][mG][mU] [mC][fU][mC][mU][mA][mA] [mA][mG][mC][mA][mG][mC][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 92[mGs][mU][mU][mA] 575 [MePhosphonate-4O- 576 [mG][mA][mG][fA][fA]mUs][fCs][fAs][fC][fC][mA] [fU][fG][mU][mG][mU] [fA][mC][mA][fC][mA][mU][mU][mG][mG][mU][mG] [mU][fC][mU][mC][mU][mA] [mA][mG][mC][mA][mG][mA][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 93[mUs][mU][mA][mG] 577 [MePhosphonate-4O- 578 [mA][mG][mA][fA][fU]mUs][fGs][fCs][fA][fC][mC] [fG][fU][mG][mU][mU] [fA][mA][mC][fA][mC][mA][mG][mG][mU][mG][mC] [mU][fU][mC][mU][mC][mU] [mA][mG][mC][mA][mG][mA][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 94[mUs][mA][mG][mA] 579 [MePhosphonate-4O- 580 [mG][mA][mA][fU][fG]mUs][fAs][fGs][fC][fA][mC] [fU][fG][mU][mU][mG] [fC][mA][mA][fC][mA][mC][mG][mU][mG][mC][mU] [mA][fU][mU][mC][mU][mC] [mA][mG][mC][mA][mG][mU][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 95[mAs][mG][mA][mG] 581 [MePhosphonate-4O- 582 [mA][mA][mU][fG][fU]mUs][fGs][fAs][fG][fC][mA] [fG][fU][mU][mG][mG] [fC][mC][mA][fA][mC][mA][mU][mG][mC][mU][mC] [mC][fA][mU][mU][mC][mU] [mA][mG][mC][mA][mG][mC][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 96[mGs][mA][mG][mA] 583 [MePhosphonate-4O- 584 [mA][mU][mG][fU][fG]mUs][fUs][fGs][fA][fG][mC] [fU][fU][mG][mG][mU] [fA][mC][mC][fA][mA][mC][mG][mC][mU][mC][mA] [mA][fC][mA][mU][mU][mC] [mA][mG][mC][mA][mG][mU][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 97[mAs][mG][mA][mA] 585 [MePhosphonate-4O- 586 [mU][mG][mU][fG][fU]mUs][fGs][fUs][fG][fA][mG] [fU][fG][mG][mU][mG] [fC][mA][mC][fC][mA][mA][mC][mU][mC][mA][mC] [mC][fA][mC][mA][mU][mU] [mA][mG][mC][mA][mG][mC][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 98[mAs][mA][mU][mG] 587 [MePhosphonate-4O- 588 [mU][mG][mU][fU][fG]mUs][fUs][fGs][fG][fU][mG] [fG][fU][mG][mC][mU] [fA][mG][mC][fA][mC][mC][mC][mA][mC][mC][mA] [mA][fA][mC][mA][mC][mA] [mA][mG][mC][mA][mG][mU][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 99[mAs][mU][mG][mU] 589 [MePhosphonate-4O- 590 [mG][mU][mU][fG][fG]mUs][fUs][fUs][fG][fG][mU] [fU][fG][mC][mU][mC] [fG][mA][mG][fC][mA][mC][mA][mC][mC][mA][mA] [mC][fA][mA][mC][mA][mC] [mA][mG][mC][mA][mG][mA][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 100[mUs][mG][mU][mG] 591 [MePhosphonate-4O- 592 [mU][mU][mG][fG][fU]mUs][fCs][fUs][fU][fG][mG] [fG][fC][mU][mC][mA] [fU][mG][mA][fG][mC][mA][mC][mC][mA][mA][mG] [mC][fC][mA][mA][mC][mA] [mA][mG][mC][mA][mG][mC][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 101[mUs][mG][mG][mU] 593 [MePhosphonate-4O- 594 [mC][mC][mA][fU][fC]mUs][fUs][fGs][fU][fU][mC] [fA][fU][mG][mA][mA] [fU][mU][mC][fA][mU][mG][mG][mA][mA][mC][mA] [mA][fU][mG][mG][mA][mC] [mA][mG][mC][mA][mG][mC][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 102[mGs][mG][mU][mC] 595 [MePhosphonate-4O- 596 [mC][mA][mU][fC][fA]mUs][fAs][fUs][fG][fU][mU] [fU][fG][mA][mA][mG] [fC][mU][mU][fC][mA][mU][mA][mA][mC][mA][mU] [mG][fA][mU][mG][mG][mA] [mA][mG][mC][mA][mG][mC][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 103[mCs][mU][mG][mA] 597 [MePhosphonate-4O- 598 [mC][mU][mU][fC][fU]mUs][fAs][fUs][fC][fU][mG] [fU][fC][mC][mU][mU] [fA][mA][mG][fG][mA][mA][mC][mA][mG][mA][mU] [mG][fA][mA][mG][mU][mC] [mA][mG][mC][mA][mG][mA][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 104[mAs][mC][mU][mU] 599 [MePhosphonate-4O- 600 [mC][mU][mU][fC][fC]mUs][fAs][fGs][fC][fA][mU] [fU][fU][mC][mA][mG] [fC][mU][mG][fA][mA][mG][mA][mU][mG][mC][mU] [mG][fA][mA][mG][mA][mA] [mA][mG][mC][mA][mG][mG][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 105[mUs][mC][mC][mU] 601 [MePhosphonate-4O- 602 [mU][mC][mA][fG][fA]mUs][fAs][fAs][fA][fA][mA] [fU][fG][mC][mU][mG] [fC][mA][mG][fC][mA][mU][mU][mU][mU][mU][mU] [mC][fU][mG][mA][mA][mG] [mA][mG][mC][mA][mG][mG][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 106[mCs][mC][mU][mU] 603 [MePhosphonate-4O- 604 [mC][mA][mG][fA][fU]mUs][fGs][fAs][fA][fA][mA] [fG][fC][mU][mG][mU] [fA][mC][mA][fG][mC][mA][mU][mU][mU][mU][mC] [mU][fC][mU][mG][mA][mA] [mA][mG][mC][mA][mG][mG][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 107[mCs][mU][mU][mC] 605 [MePhosphonate-4O- 606 [mA][mG][mA][fU][fG]mUs][fUs][fGs][fA][fA][mA] [fC][fU][mG][mU][mU] [fA][mA][mC][fA][mG][mC][mU][mU][mU][mC][mA] [mA][fU][mC][mU][mG][mA] [mA][mG][mC][mA][mG][mA][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 108[mUs][mU][mC][mA] 607 [MePhosphonate-4O- 608 [mG][mA][mU][fG][fC]mUs][fGs][fUs][fG][fA][mA] [fU][fG][mU][mU][mU] [fA][mA][mA][fC][mA][mG][mU][mU][mC][mA][mC] [mC][fA][mU][mC][mU][mG] [mA][mG][mC][mA][mG][mA][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 109[mCs][mA][mG][mA] 609 [MePhosphonate-4O- 610 [mU][mG][mC][fU][fG]mUs][fUs][fGs][fG][fU][mG] [fU][fU][mU][mU][mU] [fA][mA][mA][fA][mA][mC][mC][mA][mC][mC][mA] [mA][fG][mC][mA][mU][mC] [mA][mG][mC][mA][mG][mU][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 110[mAs][mG][mA][mU] 611 [MePhosphonate-4O- 612 [mG][mC][mU][fG][fU]mUs][fGs][fUs][fG][fG][mU] [fU][fU][mU][mU][mC] [fG][mA][mA][fA][mA][mA][mA][mC][mC][mA][mC] [mC][fA][mG][mC][mA][mU] [mA][mG][mC][mA][mG][mC][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 111[mGs][mA][mU][mG] 613 [MePhosphonate-4O- 614 [mC][mU][mG][fU][fU]mUs][fAs][fGs][fU][fG][mG] [fU][fU][mU][mC][mA] [fU][mG][mA][fA][mA][mA][mC][mC][mA][mC][mU] [mA][fC][mA][mG][mC][mA] [mA][mG][mC][mA][mG][mU][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 112[mAs][mU][mG][mC] 615 [MePhosphonate-4O- 616 [mU][mG][mU][fU][fU]mUs][fCs][fAs][fG][fU][mG] [fU][fU][mC][mA][mC] [fG][mU][mG][fA][mA][mA][mC][mA][mC][mU][mG] [mA][fA][mC][mA][mG][mC] [mA][mG][mC][mA][mG][mA][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 113[mUs][mG][mC][mU] 617 [MePhosphonate-4O- 618 [mG][mU][mU][fU][fU]mUs][fAs][fCs][fA][fG][mU] [fU][fC][mA][mC][mC] [fG][mG][mU][fG][mA][mA][mA][mC][mU][mG][mU] [mA][fA][mA][mC][mA][mG] [mA][mG][mC][mA][mG][mC][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 114[mGs][mC][mU][mG] 619 [MePhosphonate-4O- 620 [mU][mU][mU][fU][fU]mUs][fGs][fAs][fC][fA][mG] [fC][fA][mC][mC][mA] [fU][mG][mG][fU][mG][mA][mC][mU][mG][mU][mC] [mA][fA][mA][mA][mC][mA] [mA][mG][mC][mA][mG][mG][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 115[mUs][mG][mU][mU] 621 [MePhosphonate-4O- 622 [mU][mU][mU][fC][fA]mUs][fAs][fGs][fG][fA][mC] [fC][fC][mA][mC][mU] [fA][mG][mU][fG][mG][mU][mG][mU][mC][mC][mU] [mG][fA][mA][mA][mA][mA] [mA][mG][mC][mA][mG][mC][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 116[mGs][mU][mU][mU] 623 [MePhosphonate-4O- 624 [mU][mU][mC][fA][fC]mUs][fCs][fAs][fG][fG][mA] [fC][fA][mC][mU][mG] [fC][mA][mG][fU][mG][mG][mU][mC][mC][mU][mG] [mU][fG][mA][mA][mA][mA] [mA][mG][mC][mA][mG][mA][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 117[mUs][mU][mU][mU] 625 [MePhosphonate-4O- 626 [mU][mC][mA][fC][fC]mUs][fAs][fCs][fA][fG][mG] [fA][fC][mU][mG][mU] [fA][mC][mA][fG][mU][mG][mC][mC][mU][mG][mU] [mG][fU][mG][mA][mA][mA] [mA][mG][mC][mA][mG][mA][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 118[mUs][mU][mU][mU] 627 [MePhosphonate-4O- 628 [mC][mA][mC][fC][fA]mUs][fGs][fAs][fC][fA][mG] [fC][fU][mG][mU][mC] [fG][mA][mC][fA][mG][mU][mC][mU][mG][mU][mC] [mG][fG][mU][mG][mA][mA] [mA][mG][mC][mA][mG][mA][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 119[mUs][mU][mC][mA] 629 [MePhosphonate-4O- 630 [mC][mC][mA][fC][fU]mUs][fUs][fGs][fG][fA][mC] [fG][fU][mC][mC][mU] [fA][mG][mG][fA][mC][mA][mG][mU][mC][mC][mA] [mG][fU][mG][mG][mU][mG] [mA][mG][mC][mA][mG][mA][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 120[mCs][mA][mC][mC] 631 [MePhosphonate-4O- 632 [mA][mC][mU][fG][fU]mUs][fAs][fAs][fU][fG][mG] [fC][fC][mU][mG][mU] [fA][mC][mA][fG][mG][mA][mC][mC][mA][mU][mU] [mC][fA][mG][mU][mG][mG] [mA][mG][mC][mA][mG][mU][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 121[mAs][mC][mC][mA] 633 [MePhosphonate-4O- 634 [mC][mU][mG][fU][fC]mUs][fCs][fAs][fA][fU][mG] [fC][fU][mG][mU][mC] [fG][mA][mC][fA][mG][mG][mC][mA][mU][mU][mG] [mA][fC][mA][mG][mU][mG] [mA][mG][mC][mA][mG][mG][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 122[mCs][mC][mA][mC] 635 [MePhosphonate-4O- 636 [mU][mG][mU][fC][fC]mUs][fUs][fCs][fA][fA][mU] [fU][fG][mU][mC][mC] [fG][mG][mA][fC][mA][mG][mA][mU][mU][mG][mA] [mG][fA][mC][mA][mG][mU] [mA][mG][mC][mA][mG][mG][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 123[mCs][mA][mC][mU] 637 [MePhosphonate-4O- 638 [mG][mU][mC][fC][fU]mUs][fGs][fUs][fC][fA][mA] [fG][fU][mC][mC][mA] [fU][mG][mG][fA][mC][mA][mU][mU][mG][mA][mC] [mG][fG][mA][mC][mA][mG] [mA][mG][mC][mA][mG][mU][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 124[mAs][mC][mU][mG] 639 [MePhosphonate-4O- 640 [mU][mC][mC][fU][fG]mUs][fUs][fGs][fU][fC][mA] [fU][fC][mC][mA][mU] [fA][mU][mG][fG][mA][mC][mU][mG][mA][mC][mA] [mA][fG][mG][mA][mC][mA] [mA][mG][mC][mA][mG][mG][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 125[mCs][mU][mA][mA] 641 [MePhosphonate-4O- 642 [mG][mC][mU][fA][fC]mUs][fUs][fGs][fG][fU][mU] [fC][fU][mG][mA][mG] [fC][mU][mC][fA][mG][mG][mA][mA][mC][mC][mA] [mU][fA][mG][mC][mU][mU] [mA][mG][mC][mA][mG][mA][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 126[mGs][mA][mG][mG] 643 [MePhosphonate-4O- 644 [mU][mC][mC][fA][fG]mUs][fAs][fCs][fA][fA][mC] [fC][fA][mG][mA][mG] [fC][mU][mC][fU][mG][mC][mG][mU][mU][mG][mU] [mU][fG][mG][mA][mC][mC] [mA][mG][mC][mA][mG][mU][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 127[mGs][mC][mA][mG] 645 [MePhosphonate-4O- 646 [mA][mG][mG][fU][fU]mUs][fUs][fGs][fU][fC][mA] [fG][fU][mC][mC][mA] [fU][mG][mG][fA][mC][mA][mU][mG][mA][mC][mA] [mA][fC][mC][mU][mC][mU] [mA][mG][mC][mA][mG][mG][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 128[mCs][mA][mG][mA] 647 [MePhosphonate-4O- 648 [mG][mG][mU][fU][fG]mUs][fCs][fUs][fG][fU][mC] [fU][fC][mC][mA][mU] [fA][mU][mG][fG][mA][mC][mG][mA][mC][mA][mG] [mA][fA][mC][mC][mU][mC] [mA][mG][mC][mA][mG][mU][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 129[mGs][mA][mG][mG] 649 [MePhosphonate-4O- 650 [mA][mU][mG][fA][fG]mUs][fUs][fCs][fC][fA][mA] [fG][fA][mA][mC][mU] [fA][mG][mU][fU][mC][mC][mU][mU][mG][mG][mA] [mU][fC][mA][mU][mC][mC] [mA][mG][mC][mA][mG][mU][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 130[mGs][mA][mA][mC] 651 [MePhosphonate-4O- 652 [mU][mU][mU][fG][fG]mUs][fAs][fCs][fA][fA][mU] [fA][fG][mG][mA][mA] [fU][mU][mC][fC][mU][mC][mA][mU][mU][mG][mU] [mC][fA][mA][mA][mG][mU] [mA][mG][mC][mA][mG][mU][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 131[mGs][mA][mC][mG] 653 [MePhosphonate-4O- 654 [mC][mU][mC][fU][fU]mUs][fGs][fUs][fA][fA][mU] [fC][fA][mG][mC][mU] [fA][mG][mC][fU][mG][mA][mA][mU][mU][mA][mC] [mA][fG][mA][mG][mC][mG] [mA][mG][mC][mA][mG][mU][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 132[mAs][mC][mG][mC] 655 [MePhosphonate-4O- 656 [mU][mC][mU][fU][fC]mUs][fUs][fGs][fU][fA][mA] [fA][fG][mC][mU][mA] [fU][mA][mG][fC][mU][mG][mU][mU][mA][mC][mA] [mA][fA][mG][mA][mG][mC] [mA][mG][mC][mA][mG][mG][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 133[mCs][mG][mC][mU] 657 [MePhosphonate-4O- 658 [mC][mU][mU][fC][fA]mUs][fUs][fUs][fG][fU][mA] [fG][fC][mU][mA][mU] [fA][mU][mA][fG][mC][mU][mU][mA][mC][mA][mA] [mG][fA][mA][mG][mA][mG] [mA][mG][mC][mA][mG][mC][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 134[mGs][mC][mU][mC] 659 [MePhosphonate-4O- 660 [mU][mU][mC][fA][fG]mUs][fGs][fUs][fU][fG][mU] [fC][fU][mA][mU][mU] [fA][mA][mU][fA][mG][mC][mA][mC][mA][mA][mC] [mU][fG][mA][mA][mG][mA] [mA][mG][mC][mA][mG][mG][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 135[mCs][mU][mC][mU] 661 [MePhosphonate-4O- 662 [mU][mC][mA][fG][fC]mUs][fUs][fGs][fU][fU][mG] [fU][fA][mU][mU][mA] [fU][mA][mA][fU][mA][mG][mC][mA][mA][mC][mA] [mC][fU][mG][mA][mA][mG] [mA][mG][mC][mA][mG][mA][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 136[mUs][mC][mU][mU] 663 [MePhosphonate-4O- 664 [mC][mA][mG][fC][fU]mUs][fAs][fUs][fG][fU][mU] [fA][fU][mU][mA][mC] [fG][mU][mA][fA][mU][mA][mA][mA][mC][mA][mU] [mG][fC][mU][mG][mA][mA] [mA][mG][mC][mA][mG][mG][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 137[mCs][mU][mU][mC] 665 [MePhosphonate-4O- 666 [mA][mG][mC][fU][fA]mUs][fGs][fAs][fU][fG][mU] [fU][fU][mA][mC][mA] [fU][mG][mU][fA][mA][mU][mA][mC][mA][mU][mC] [mA][fG][mC][mU][mG][mA] [mA][mG][mC][mA][mG][mA][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 138[mUs][mU][mC][mA] 667 [MePhosphonate-4O- 668 [mG][mC][mU][fA][fU]mUs][fUs][fGs][fA][fU][mG] [fU][fA][mC][mA][mA] [fU][mU][mG][fU][mA][mA][mC][mA][mU][mC][mA] [mU][fA][mG][mC][mU][mG] [mA][mG][mC][mA][mG][mA][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 139[mCs][mC][mA][mG] 669 [MePhosphonate-4O- 670 [mC][mC][mU][fG][fA]mUs][fGs][fCs][fA][fG][mG] [fC][fC][mU][mC][mA] [fU][mG][mA][fG][mG][mU][mC][mC][mU][mG][mC] [mC][fA][mG][mG][mC][mU] [mA][mG][mC][mA][mG][mG][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 140[mCs][mA][mG][mC] 671 [MePhosphonate-4O- 672 [mC][mU][mG][fA][fC]mUs][fAs][fGs][fC][fA][mG] [fC][fU][mC][mA][mC] [fG][mU][mG][fA][mG][mG][mC][mU][mG][mC][mU] [mU][fC][mA][mG][mG][mC] [mA][mG][mC][mA][mG][mU][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 141[mAs][mG][mC][mC] 673 [MePhosphonate-4O- 674 [mU][mG][mA][fC][fC]mUs][fAs][fAs][fG][fC][mA] [fU][fC][mA][mC][mC] [fG][mG][mU][fG][mA][mG][mU][mG][mC][mU][mU] [mG][fU][mC][mA][mG][mG] [mA][mG][mC][mA][mG][mC][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 142[mGs][mC][mC][mU] 675 [MePhosphonate-4O- 676 [mG][mA][mC][fC][fU]mUs][fUs][fAs][fA][fG][mC] [fC][fA][mC][mC][mU] [fA][mG][mG][fU][mG][mA][mG][mC][mU][mU][mA] [mG][fG][mU][mC][mA][mG] [mA][mG][mC][mA][mG][mG][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 143[mCs][mC][mU][mG] 677 [MePhosphonate-4O- 678 [mA][mC][mC][fU][fC]mUs][fUs][fUs][fA][fA][mG] [fA][fC][mC][mU][mG] [fC][mA][mG][fG][mU][mG][mC][mU][mU][mA][mA] [mA][fG][mG][mU][mC][mA] [mA][mG][mC][mA][mG][mG][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 144[mCs][mU][mG][mA] 679 [MePhosphonate-4O- 680 [mC][mC][mU][fC][fA]mUs][fAs][fUs][fU][fA][mA] [fC][fC][mU][mG][mC] [fG][mC][mA][fG][mG][mU][mU][mU][mA][mA][mU] [mG][fA][mG][mG][mU][mC] [mA][mG][mC][mA][mG][mA][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 145[mUs][mG][mA][mC] 681 [MePhosphonate-4O- 682 [mC][mU][mC][fA][fC]mUs][fAs][fAs][fU][fU][mA] [fC][fU][mG][mC][mU] [fA][mG][mC][fA][mG][mG][mU][mA][mA][mU][mU] [mU][fG][mA][mG][mG][mU] [mA][mG][mC][mA][mG][mC][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 146[mGs][mA][mC][mC] 683 [MePhosphonate-4O- 684 [mU][mC][mA][fC][fC]mUs][fCs][fAs][fA][fU][mU] [fU][fG][mC][mU][mU] [fA][mA][mG][fC][mA][mG][mA][mA][mU][mU][mG] [mG][fU][mG][mA][mG][mG] [mA][mG][mC][mA][mG][mU][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 147[mAs][mC][mC][mU] 685 [MePhosphonate-4O- 686 [mC][mA][mC][fC][fU]mUs][fUs][fCs][fA][fA][mU] [fG][fC][mU][mU][mA] [fU][mA][mA][fG][mC][mA][mA][mU][mU][mG][mA] [mG][fG][mU][mG][mA][mG] [mA][mG][mC][mA][mG][mG][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 148[mCs][mC][mU][mC] 687 [MePhosphonate-4O- 688 [mA][mC][mC][fU][fG]mUs][fGs][fUs][fC][fA][mA] [fC][fU][mU][mA][mA] [fU][mU][mA][fA][mG][mC][mU][mU][mG][mA][mC] [mA][fG][mG][mU][mG][mA] [mA][mG][mC][mA][mG][mG][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 149[mCs][mU][mC][mA] 689 [MePhosphonate-4O- 690 [mC][mC][mU][fG][fC]mUs][fUs][fGs][fU][fC][mA] [fU][fU][mA][mA][mU] [fA][mU][mU][fA][mA][mG][mU][mG][mA][mC][mA] [mC][fA][mG][mG][mU][mG] [mA][mG][mC][mA][mG][mA][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 150[mUs][mC][mA][mC] 691 [MePhosphonate-4O- 692 [mC][mU][mG][fC][fU]mUs][fGs][fUs][fG][fU][mC] [fU][fA][mA][mU][mU] [fA][mA][mU][fU][mA][mA][mG][mA][mC][mA][mC] [mG][fC][mA][mG][mG][mU] [mA][mG][mC][mA][mG][mG][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 151[mCs][mA][mC][mC] 693 [MePhosphonate-4O- 694 [mU][mG][mC][fU][fU]mUs][fGs][fGs][fU][fG][mU] [fA][fA][mU][mU][mG] [fC][mA][mA][fU][mU][mA][mA][mC][mA][mC][mC] [mA][fG][mC][mA][mG][mG] [mA][mG][mC][mA][mG][mU][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 152[mAs][mC][mC][mU] 695 [MePhosphonate-4O- 696 [mG][mC][mU][fU][fA]mUs][fUs][fGs][fG][fU][mG] [fA][fU][mU][mG][mA] [fU][mC][mA][fA][mU][mU][mC][mA][mC][mC][mA] [mA][fA][mG][mC][mA][mG] [mA][mG][mC][mA][mG][mG][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 153[mCs][mC][mU][mG] 697 [MePhosphonate-4O- 698 [mC][mU][mU][fA][fA]mUs][fUs][fUs][fG][fG][mU] [fU][fU][mG][mA][mC] [fG][mU][mC][fA][mA][mU][mA][mC][mC][mA][mA] [mU][fA][mA][mG][mC][mA] [mA][mG][mC][mA][mG][mG][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 154[mCs][mU][mG][mC] 699 [MePhosphonate-4O- 700 [mU][mU][mA][fA][fU]mUs][fGs][fUs][fU][fG][mG] [fU][fG][mA][mC][mA] [fU][mG][mU][fC][mA][mA][mC][mC][mA][mA][mC] [mU][fU][mA][mA][mG][mC] [mA][mG][mC][mA][mG][mA][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 155[mUs][mG][mC][mU] 701 [MePhosphonate-4O- 702 [mU][mA][mA][fU][fU]mUs][fAs][fGs][fU][fU][mG] [fG][fA][mC][mA][mC] [fG][mU][mG][fU][mC][mA][mC][mA][mA][mC][mU] [mA][fU][mU][mA][mA][mG] [mA][mG][mC][mA][mG][mC][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 156[mGs][mC][mU][mU] 703 [MePhosphonate-4O- 704 [mA][mA][mU][fU][fG]mUs][fAs][fAs][fG][fU][mU] [fA][fC][mA][mC][mC] [fG][mG][mU][fG][mU][mC][mA][mA][mC][mU][mU] [mA][fA][mU][mU][mA][mA] [mA][mG][mC][mA][mG][mG][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 157[mCs][mU][mU][mA] 705 [MePhosphonate-4O- 706 [mA][mU][mU][fG][fA]mUs][fAs][fAs][fA][fG][mU] [fC][fA][mC][mC][mA] [fU][mG][mG][fU][mG][mU][mA][mC][mU][mU][mU] [mC][fA][mA][mU][mU][mA] [mA][mG][mC][mA][mG][mA][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 158[mUs][mU][mA][mA] 707 [MePhosphonate-4O- 708 [mU][mU][mG][fA][fC]mUs][fAs][fAs][fA][fA][mG] [fA][fC][mC][mA][mA] [fU][mU][mG][fG][mU][mG][mC][mU][mU][mU][mU] [mU][fC][mA][mA][mU][mU] [mA][mG][mC][mA][mG][mA][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 159[mUs][mA][mA][mU] 709 [MePhosphonate-4O- 710 [mU][mG][mA][fC][fA]mUs][fGs][fAs][fA][fA][mA] [fC][fC][mA][mA][mC] [fG][mU][mU][fG][mG][mU][mU][mU][mU][mU][mC] [mG][fU][mC][mA][mA][mU] [mA][mG][mC][mA][mG][mU][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 160[mAs][mU][mU][mG] 711 [MePhosphonate-4O- 712 [mA][mA][mG][fG][fG]mUs][fAs][fGs][fC][fA][mC] [fG][fU][mG][mC][mU] [fA][mG][mC][fA][mC][mC][mG][mU][mG][mC][mU] [mC][fC][mU][mU][mC][mA] [mA][mG][mC][mA][mG][mA][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 161[mCs][mU][mU][mG] 713 [MePhosphonate-4O- 714 [mG][mA][mC][fA][fA]mUs][fCs][fAs][fC][fA][mA] [fA][fA][mG][mG][mA] [fU][mC][mC][fU][mU][mU][mU][mU][mG][mU][mG] [mU][fG][mU][mC][mC][mA] [mA][mG][mC][mA][mG][mA][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 162[mUs][mU][mG][mG] 715 [MePhosphonate-4O- 716 [mA][mC][mA][fA][fA]mUs][fCs][fCs][fA][fC][mA] [fA][fG][mG][mA][mU] [fA][mU][mC][fC][mU][mU][mU][mG][mU][mG][mG] [mU][fU][mG][mU][mC][mC] [mA][mG][mC][mA][mG][mA][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 163[mUs][mC][mA][mA] 717 [MePhosphonate-4O- 718 [mC][mG][mG][fU][fU]mUs][fAs][fAs][fA][fU][mC] [fC][fC][mC][mU][mU] [fA][mA][mG][fG][mG][mA][mG][mA][mU][mU][mU] [mA][fC][mC][mG][mU][mU] [mA][mG][mC][mA][mG][mG][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 164[mCs][mA][mA][mC] 719 [MePhosphonate-4O- 720 [mG][mG][mU][fU][fC]mUs][fGs][fAs][fA][fA][mU] [fC][fC][mU][mU][mG] [fC][mA][mA][fG][mG][mG][mA][mU][mU][mU][mC] [mA][fA][mC][mC][mG][mU] [mA][mG][mC][mA][mG][mU][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 165[mAs][mA][mC][mG] 721 [MePhosphonate-4O- 722 [mG][mU][mU][fC][fC]mUs][fAs][fGs][fA][fA][mA] [fC][fU][mU][mG][mA] [fU][mC][mA][fA][mG][mG][mU][mU][mU][mC][mU] [mG][fA][mA][mC][mC][mG] [mA][mG][mC][mA][mG][mU][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 166[mAs][mC][mG][mG] 723 [MePhosphonate-4O- 724 [mU][mU][mC][fC][fC]mUs][fAs][fAs][fG][fA][mA] [fU][fU][mG][mA][mU] [fA][mU][mC][fA][mA][mG][mU][mU][mC][mU][mU] [mG][fG][mA][mA][mC][mC] [mA][mG][mC][mA][mG][mG][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 167[mGs][mU][mA][mC] 725 [MePhosphonate-4O- 726 [mA][mU][mU][fG][fA]mUs][fCs][fAs][fU][fG][mG] [fC][fC][mA][mG][mA] [fU][mC][mU][fG][mG][mU][mC][mC][mA][mU][mG] [mC][fA][mA][mU][mG][mU] [mA][mG][mC][mA][mG][mA][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 168[mAs][mC][mC][mU] 727 [MePhosphonate-4O- 728 [mG][mU][mA][fC][fC]mUs][fCs][fAs][fC][fA][mG] [fA][fC][mC][mU][mC] [fG][mA][mG][fG][mU][mG][mC][mU][mG][mU][mG] [mG][fU][mA][mC][mA][mG] [mA][mG][mC][mA][mG][mG][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 169[mCs][mC][mU][mG] 729 [MePhosphonate-4O- 730 [mU][mA][mC][fC][fA]mUs][fAs][fCs][fA][fC][mA] [fC][fC][mU][mC][mC] [fG][mG][mA][fG][mG][mU][mU][mG][mU][mG][mU] [mG][fG][mU][mA][mC][mA] [mA][mG][mC][mA][mG][mG][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 170[mGs][mU][mA][mC] 731 [MePhosphonate-4O- 732 [mC][mA][mC][fC][fU]mUs][fAs][fUs][fG][fA][mC] [fC][fC][mU][mG][mU] [fA][mC][mA][fG][mG][mA][mG][mU][mC][mA][mU] [mG][fG][mU][mG][mG][mU] [mA][mG][mC][mA][mG][mA][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 171[mGs][mC][mA][mC] 733 [MePhosphonate-4O- 734 [mA][mG][mG][fC][fA]mUs][fUs][fAs][fG][fA][mA] [fU][fC][mA][mA][mG] [fC][mU][mU][fG][mA][mU][mU][mU][mC][mU][mA] [mG][fC][mC][mU][mG][mU] [mA][mG][mC][mA][mG][mG][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 172[mAs][mC][mA][mG] 735 [MePhosphonate-4O- 736 [mG][mC][mA][fU][fC]mUs][fAs][fGs][fU][fA][mG] [fA][fA][mG][mU][mU] [fA][mA][mC][fU][mU][mG][mC][mU][mA][mC][mU] [mA][fU][mG][mC][mC][mU] [mA][mG][mC][mA][mG][mG][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 173[mCs][mA][mG][mG] 737 [MePhosphonate-4O- 738 [mC][mA][mU][fC][fA]mUs][fGs][fAs][fG][fU][mA] [fA][fG][mU][mU][mC] [fG][mA][mA][fC][mU][mU][mU][mA][mC][mU][mC] [mG][fA][mU][mG][mC][mC] [mA][mG][mC][mA][mG][mU][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 174[mAs][mG][mG][mC] 739 [MePhosphonate-4O- 740 [mA][mU][mC][fA][fA]mUs][fGs][fGs][fA][fG][mU] [fG][fU][mU][mC][mU] [fA][mG][mA][fA][mC][mU][mA][mC][mU][mC][mC] [mU][fG][mA][mU][mG][mC] [mA][mG][mC][mA][mG][mC][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 175[mGs][mG][mC][mA] 741 [MePhosphonate-4O- 742 [mU][mC][mA][fA][fG]mUs][fUs][fGs][fG][fA][mG] [fU][fU][mC][mU][mA] [fU][mA][mG][fA][mA][mC][mC][mU][mC][mC][mA] [mU][fU][mG][mA][mU][mG] [mA][mG][mC][mA][mG][mC][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 176[mGs][mC][mA][mU] 743 [MePhosphonate-4O- 744 [mC][mA][mA][fG][fU]mUs][fAs][fUs][fG][fG][mA] [fU][fC][mU][mA][mC] [fG][mU][mA][fG][mA][mA][mU][mC][mC][mA][mU] [mC][fU][mU][mG][mA][mU] [mA][mG][mC][mA][mG][mG][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 177[mCs][mA][mU][mC] 745 [MePhosphonate-4O- 746 [mA][mA][mG][fU][fU]mUs][fAs][fAs][fU][fG][mG] [fC][fU][mA][mC][mU] [fA][mG][mU][fA][mG][mA][mC][mC][mA][mU][mU] [mA][fC][mU][mU][mG][mA] [mA][mG][mC][mA][mG][mU][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 178[mAs][mU][mC][mA] 747 [MePhosphonate-4O- 748 [mA][mG][mU][fU][fC]mUs][fGs][fAs][fA][fU][mG] [fU][fA][mC][mU][mC] [fG][mA][mG][fU][mA][mG][mC][mA][mU][mU][mC] [mA][fA][mC][mU][mU][mG] [mA][mG][mC][mA][mG][mA][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 179[mUs][mC][mA][mA] 749 [MePhosphonate-4O- 750 [mG][mU][mU][fC][fU]mUs][fUs][fGs][fA][fA][mU] [fA][fC][mU][mC][mC] [fG][mG][mA][fG][mU][mA][mA][mU][mU][mC][mA] [mG][fA][mA][mC][mU][mU] [mA][mG][mC][mA][mG][mG][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 180[mCs][mA][mA][mG] 751 [MePhosphonate-4O- 752 [mU][mU][mC][fU][fA]mUs][fCs][fUs][fG][fA][mA] [fC][fU][mC][mC][mA] [fU][mG][mG][fA][mG][mU][mU][mU][mC][mA][mG] [mA][fG][mA][mA][mC][mU] [mA][mG][mC][mA][mG][mU][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 181[mAs][mA][mG][mU] 753 [MePhosphonate-4O- 754 [mU][mC][mU][fA][fC]mUs][fGs][fCs][fU][fG][mA] [fU][fC][mC][mA][mU] [fA][mU][mG][fG][mA][mG][mU][mC][mA][mG][mC] [mU][fA][mG][mA][mA][mC] [mA][mG][mC][mA][mG][mU][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 182[mAs][mG][mU][mU] 755 [MePhosphonate-4O- 756 [mC][mU][mA][fC][fU]mUs][fUs][fGs][fC][fU][mG] [fC][fC][mA][mU][mU] [fA][mA][mU][fG][mG][mA][mC][mA][mG][mC][mA] [mG][fU][mA][mG][mA][mA] [mA][mG][mC][mA][mG][mC][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 183[mGs][mU][mU][mC] 757 [MePhosphonate-4O- 758 [mU][mA][mC][fU][fC]mUs][fCs][fUs][fG][fC][mU] [fC][fA][mU][mU][mC] [fG][mA][mA][fU][mG][mG][mA][mG][mC][mA][mG] [mA][fG][mU][mA][mG][mA] [mA][mG][mC][mA][mG][mA][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 184[mGs][mU][mG][mU] 759 [MePhosphonate-4O- 760 [mC][mA][mU][fC][fU]mUs][fAs][fGs][fG][fU][mU] [fC][fA][mG][mA][mC] [fG][mU][mC][fU][mG][mA][mA][mA][mC][mC][mU] [mG][fA][mU][mG][mA][mC] [mA][mG][mC][mA][mG][mA][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 185[mCs][mA][mU][mC] 761 [MePhosphonate-4O- 762 [mU][mC][mA][fG][fA]mUs][fCs][fAs][fG][fC][mA] [fC][fA][mA][mC][mC] [fG][mG][mU][fU][mG][mU][mU][mG][mC][mU][mG] [mC][fU][mG][mA][mG][mA] [mA][mG][mC][mA][mG][mU][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 186[mUs][mC][mA][mG] 763 [MePhosphonate-4O- 764 [mA][mC][mA][fA][fC]mUs][fUs][fCs][fA][fC][mC] [fC][fU][mG][mC][mU] [fA][mG][mC][fA][mG][mG][mG][mG][mU][mG][mA] [mU][fU][mG][mU][mC][mU] [mA][mG][mC][mA][mG][mG][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 187[mCs][mG][mG][mG] 765 [MePhosphonate-4O- 766 [mG][mA][mC][fC][fU]mUs][fUs][fGs][fU][fC][mU] [fG][fU][mU][mA][mC] [fG][mU][mA][fA][mC][mA][mA][mG][mA][mC][mA] [mG][fG][mU][mC][mC][mC] [mA][mG][mC][mA][mG][mC][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 188[mGs][mA][mC][mA] 767 [MePhosphonate-4O- 768 [mA][mC][mG][fC][fU]mUs][fAs][fGs][fA][fC][mA] [fG][fC][mC][mA][mU] [fA][mU][mG][fG][mC][mA][mU][mG][mU][mC][mU] [mG][fC][mG][mU][mU][mG] [mA][mG][mC][mA][mG][mU][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 189[mGs][mC][mU][mG] 769 [MePhosphonate-4O- 770 [mC][mC][mU][fC][fC]mUs][fAs][fUs][fU][fA][mC] [fU][fG][mA][mC][mU] [fA][mG][mU][fC][mA][mG][mG][mU][mA][mA][mU] [mG][fA][mG][mG][mC][mA] [mA][mG][mC][mA][mG][mG][mCs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 190[mCs][mU][mG][mC] 771 [MePhosphonate-4O- 772 [mC][mU][mC][fC][fU]mUs][fUs][fAs][fU][fU][mA] [fG][fA][mC][mU][mG] [fC][mA][mG][fU][mC][mA][mU][mA][mA][mU][mA] [mG][fG][mA][mG][mG][mC] [mA][mG][mC][mA][mG][mA][mGs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 191[mUs][mA][mA][mU] 773 [MePhosphonate-4O- 774 [mA][mU][mU][fA][fA]mUs][fUs][fUs][fA][fA][mA] [fA][fC][mU][mU][mU] [fA][mA][mA][fG][mU][mU][mU][mU][mU][mA][mA] [mU][fA][mA][mU][mA][mU] [mA][mG][mC][mA][mG][mU][mAs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC] 192[mAs][mA][mU][mA] 775 [MePhosphonate-4O- 776 [mU][mU][mA][fA][fA]mUs][fUs][fUs][fU][fA][mA] [fC][fU][mU][mU][mU] [fA][mA][mA][fA][mG][mU][mU][mU][mA][mA][mA] [mU][fU][mA][mA][mU][mA] [mA][mG][mC][mA][mG][mU][mUs][mGs][mG] [mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG] [mG][mC][mU][mG][mC]

The human hepatocyte 3D spheroid-based assay described in Example 2 isrepeated with the GalXC™-SCAP oligonucleotides of Table 4, the resultsof which are shown in Table 5.

TABLE 5 GalXC ™-SCAP Oligonucleotide SCAP mRNA Knockdown in 3D HumanSpheroids; administered at 100 nM for 7 Days; -5′ and -3′ Assays % mRNARemaining (normalized to Hs HPRT-517 (HEX) and Hs SFRS9-569 (HEX) vsmock control). HPRT-517 (HEX) SFRS9-569 (HEX) Average GalXC ™- % mRNA %% mRNA % % mRNA % SCAP Remaining SEM Remaining SEM Remaining SEM 1 67.311.5 66.3 12.0 66.8 0.7 2 26.3 12.1 17.7 7.8 22.0 6.1 3 43.5 4.7 48.05.6 45.7 3.2 4 64.2 12.4 55.8 13.6 60.0 6.0 5 73.5 10.2 86.3 11.0 79.99.0 6 59.8 10.1 94.1 11.3 77.0 24.3 7 43.9 7.8 60.8 11.1 52.3 11.9 894.4 26.7 110.7 19.3 102.6 11.5 9 32.7 5.0 53.7 10.3 43.2 14.8 10 44.13.3 61.7 5.1 52.9 12.4 11 77.1 21.9 97.5 18.5 87.3 14.4 12 64.3 54.472.5 53.6 68.4 5.8 13 6.4 1.9 36.3 6.9 21.4 21.1 14 80.4 16.1 104.2 17.892.3 16.8 15 87.1 10.4 111.2 12.5 99.2 17.0 16 91.3 19.6 106.5 23.2 98.910.8 17 64.3 6.3 101.3 14.1 82.8 26.2 18 99.0 18.7 101.6 28.4 100.3 1.819 75.7 11.1 90.1 16.0 82.9 10.2 20 35.2 7.4 45.6 12.1 40.4 7.3 21 32.77.0 35.0 11.0 33.9 1.6 22 49.3 4.8 61.6 5.2 55.4 8.7 23 76.2 16.4 86.020.5 81.1 6.9 24 22.7 4.6 38.0 7.1 30.4 10.8 25 110.6 19.0 103.6 19.7107.1 4.9 26 57.2 16.0 67.9 16.1 62.6 7.6 27 66.4 11.2 78.6 11.9 72.58.6 28 100.0 22.1 134.8 21.6 117.4 24.6 29 53.2 13.3 58.1 13.8 55.6 3.530 42.7 10.6 66.5 15.3 54.6 16.8 31 46.2 5.8 89.9 12.6 68.0 31.0 32 59.912.1 73.3 11.8 66.6 9.5 33 29.4 5.5 38.5 7.4 33.9 6.4 34 92.3 19.3 127.018.3 109.7 24.6 35 95.5 25.6 120.3 27.5 107.9 17.5 36 69.9 20.9 102.133.2 86.0 22.8 37 57.1 20.6 82.3 22.0 69.7 17.8 38 53.7 12.9 70.4 14.862.1 11.8 39 87.5 19.1 107.1 26.1 97.3 13.8 40 67.7 16.2 93.7 26.9 80.718.4 41 78.5 16.1 94.7 14.0 86.6 11.5 42 43.0 5.8 39.2 5.7 41.1 2.7 4325.8 4.7 29.7 5.4 27.7 2.8 44 55.4 7.6 72.2 8.6 63.8 11.9 45 78.0 7.7101.9 7.2 89.9 16.9 46 53.4 38.0 118.6 56.2 86.0 46.1 47 69.1 10.8 87.413.8 78.2 12.9 48 155.7 107.9 73.6 57.4 114.7 58.0 49 57.1 9.2 62.7 11.959.9 3.9 50 61.2 6.3 76.6 7.7 68.9 10.9 51 37.8 6.3 38.1 7.6 38.0 0.2 5232.6 5.7 35.9 8.4 34.2 2.3 53 50.4 3.8 60.5 6.5 55.4 7.1 54 41.8 9.451.4 12.0 46.6 6.8 55 58.5 8.0 57.5 11.4 58.0 0.7 56 82.7 14.0 86.3 17.984.5 2.5 57 59.9 5.9 64.3 5.5 62.1 3.1 58 90.3 11.2 87.7 10.9 89.0 1.959 78.7 8.1 83.8 7.3 81.3 3.6 60 40.2 8.8 35.7 8.0 37.9 3.2 61 46.5 8.649.6 8.7 48.1 2.2 62 33.4 6.5 38.3 7.2 35.9 3.5 63 30.7 5.0 41.2 6.536.0 7.4 64 60.0 11.9 48.1 9.6 54.1 8.4 65 39.0 5.5 39.0 6.1 39.0 0.1 6630.3 3.4 25.6 3.6 28.0 3.3 67 14.2 3.6 17.0 3.7 15.6 1.9 68 33.4 5.228.6 5.2 31.0 3.4 69 27.9 1.9 32.7 4.3 30.3 3.4 70 11.0 1.2 12.4 1.711.7 1.0 71 74.5 6.9 87.7 7.5 81.1 9.3 72 88.7 7.1 83.0 7.8 85.8 4.1 7341.3 12.4 46.3 5.4 43.8 3.5 74 77.9 28.7 99.8 29.7 88.9 15.4 75 45.820.7 86.2 21.2 66.0 28.6 76 81.9 13.4 86.9 15.8 84.4 3.5 77 94.3 14.9105.8 13.8 100.0 8.2 78 73.6 10.1 84.8 12.6 79.2 7.9 79 41.2 8.6 47.39.2 44.2 4.3 80 68.6 6.7 91.5 8.5 80.0 16.2 81 60.5 5.8 67.7 10.2 64.15.1 82 49.4 21.3 49.5 12.3 49.5 0.1 83 65.4 7.3 85.3 10.4 75.4 14.1 8466.2 10.2 60.9 11.2 63.5 3.8 85 67.7 4.9 78.3 6.6 73.0 7.5 86 58.2 7.371.3 9.5 64.7 9.3 87 66.2 4.9 79.2 8.8 72.7 9.2 88 82.1 11.0 94.1 15.988.1 8.5 89 83.4 56.0 48.4 20.8 65.9 24.8 90 67.7 9.7 67.3 9.1 67.5 0.391 56.9 23.8 55.5 22.0 56.2 1.0 92 83.5 8.7 84.2 9.2 83.9 0.4 93 49.24.3 45.6 5.4 47.4 2.5 94 62.6 6.2 79.6 9.5 71.1 12.1 95 43.8 9.1 48.410.3 46.1 3.2 96 47.6 6.8 48.7 6.1 48.1 0.7 97 127.0 110.9 66.2 54.396.6 43.0 98 56.9 5.5 68.5 5.4 62.7 8.2 99 83.0 6.1 84.6 9.6 83.8 1.1100 72.1 25.4 137.4 41.3 104.7 46.2 101 39.0 6.9 48.5 9.0 43.8 6.7 10255.8 6.4 74.0 10.7 64.9 12.9 103 21.6 10.5 41.7 15.9 31.6 14.2 104 12.67.3 15.9 11.4 14.2 2.3 105 17.6 3.1 60.0 6.8 38.8 30.0 106 3.3 0.6 13.95.1 8.6 7.5 107 6.4 1.5 22.9 5.2 14.7 11.7 108 17.7 2.9 44.6 8.3 31.119.1 109 15.8 10.0 57.0 30.9 36.4 29.2 110 12.1 1.4 49.2 5.2 30.6 26.2111 27.8 6.9 50.5 12.1 39.2 16.1 112 28.8 15.5 64.5 27.3 46.7 25.2 11320.7 3.0 40.6 5.4 30.6 14.1 114 37.7 17.1 71.2 22.6 54.4 23.7 115 17.56.2 30.2 11.8 23.9 9.0 116 63.9 9.2 86.9 11.8 75.4 16.3 117 30.5 2.939.4 4.1 34.9 6.3 118 43.9 10.9 61.8 14.2 52.9 12.7 119 44.0 5.2 57.48.7 50.7 9.5 120 38.1 12.1 55.8 15.3 46.9 12.5 121 59.4 29.3 86.1 35.772.8 18.9 122 62.6 12.2 81.9 13.3 72.3 13.7 123 55.7 19.8 85.2 30.5 70.520.8 124 35.2 8.0 80.9 21.6 58.1 32.4 125 57.3 8.2 71.1 7.1 64.2 9.7 12686.3 21.0 88.9 25.2 87.6 1.8 127 83.4 15.4 106.5 22.9 94.9 16.3 128119.6 61.8 78.2 59.0 98.9 29.3 129 88.0 14.9 94.3 16.8 91.2 4.4 130 94.368.0 83.8 54.1 89.1 7.5 131 50.2 17.0 66.4 14.8 58.3 11.5 132 50.9 5.147.6 4.6 49.3 2.4 133 33.1 18.1 45.3 13.4 39.2 8.6 134 38.7 21.1 61.925.4 50.3 16.4 135 — — 52.6 31.5 52.6 32.5 136 34.2 10.0 37.6 10.1 35.92.4 137 92.8 24.3 92.7 21.9 92.8 0.1 138 49.7 14.6 48.9 11.4 49.3 0.6139 74.2 11.0 86.8 11.9 80.5 8.9 140 91.6 25.4 92.3 27.1 91.9 0.5 14161.9 7.5 64.1 8.2 63.0 1.6 142 60.3 10.8 72.7 17.4 66.5 8.8 143 136.656.4 55.2 41.9 95.9 57.6 144 121.2 42.0 59.0 29.7 90.1 44.0 145 83.510.9 87.6 12.3 85.5 2.9 146 73.6 7.3 67.9 4.9 70.7 4.0 147 104.3 16.477.3 8.5 90.8 19.1 148 84.2 12.7 81.0 10.8 82.6 2.3 149 53.4 9.7 58.511.8 55.9 3.6 150 77.3 25.8 69.8 23.9 73.5 5.4 151 108.2 43.9 120.3 39.8114.3 8.5 152 66.5 12.1 56.5 11.2 61.5 7.1 153 43.3 6.4 57.9 11.6 50.610.4 154 78.7 8.2 78.4 9.0 78.5 0.2 155 86.6 8.1 69.9 7.7 78.3 11.8 15636.0 4.9 40.7 4.3 38.3 3.3 157 39.6 3.7 31.2 3.2 35.4 5.9 158 25.2 11.526.4 11.8 25.8 0.8 159 24.6 7.4 22.5 6.1 23.6 1.5 160 101.4 17.4 86.116.5 93.7 10.8 161 90.3 12.2 65.3 16.3 77.8 17.7 162 74.4 11.1 66.2 12.670.3 5.8 163 19.5 2.8 10.2 2.2 14.8 6.6 164 23.3 2.6 18.1 3.6 20.7 3.6165 16.7 7.7 10.4 4.2 13.6 4.5 166 27.2 4.2 23.2 2.7 25.2 2.8 167 87.010.1 77.9 8.7 82.5 6.4 168 116.7 39.9 89.4 27.8 103.1 19.3 169 100.9 7.787.6 5.3 94.2 9.4 170 95.2 22.4 83.3 18.1 89.3 8.4 171 47.4 10.3 42.29.8 44.8 3.7 172 63.3 14.3 43.2 10.7 53.2 14.2 173 55.6 10.5 48.9 8.352.2 4.7 174 45.5 6.5 38.9 7.5 42.2 4.6 175 45.5 15.1 33.2 13.4 39.4 8.7176 30.7 7.3 30.2 6.2 30.4 0.3 177 46.4 7.4 45.0 5.9 45.7 1.0 178 38.94.9 41.3 5.2 40.1 1.7 179 63.6 12.7 49.6 14.6 56.6 9.9 180 80.4 9.9 72.28.1 76.3 5.8 181 68.2 7.5 50.7 7.1 59.4 12.4 182 37.9 22.9 53.0 24.545.5 10.7 183 93.8 20.0 89.0 17.9 91.4 3.4 184 95.3 21.4 132.1 24.0113.7 26.0 185 77.4 5.5 79.3 9.4 78.3 1.4 186 55.1 3.5 39.1 4.1 47.111.4 187 69.3 37.6 78.8 30.9 74.0 6.7 188 81.2 15.0 66.2 14.1 73.7 10.6189 57.2 15.8 58.6 12.4 57.9 1.0 190 69.4 29.6 70.6 28.9 70.0 0.9 19177.3 8.0 62.2 7.6 69.7 10.7 192 79.9 42.5 67.8 28.7 73.9 8.5

In Vivo Function

Example 4: RNAi Oligonucleotide Modulation of SCAP Activity InVivo—GalXC™-Based Compounds

Mouse studies: The GalXC™-SCAP oligonucleotides, as listed in Tables 3(unmodified) and 4 (modified), are evaluated in hydrodynamic injection(HDI) mouse model. In the HDI studies, mice are engineered totransiently express human SCAP mRNA in hepatocytes. A GalXC™-SCAPoligonucleotide control (GalXC™-SCAP oligonucleotide no. 42; see, SEQ IDNOs: 475 and 476) is used as a benchmark control. Briefly, 6-8-week-oldfemale CD-1 mice are treated SQ with a GalXC-™SCAP oligonucleotide at adose level of 2 mg/kg. Three days later (72 hr.), the mice are HDI witha DNA plasmid encoding the full human SCAP gene under control of aubiquitous cytomegalovirus (CMV) promoter sequence. One day afterintroduction of the plasmid, liver samples are collected. Total RNAderived from these mice are subjected to qRT-PCR analysis for SCAP mRNA,relative to mice treated only with an identical volume of PBS. Thevalues are normalized for transfection efficiency using the NeoR geneincluded on the plasmid.

As shown in Tables 6 to 8, a number of GalXC™-SCAP oligonucleotidestested inhibited SCAP activity, as determined by a reduced amount ofSCAP mRNA in liver samples from oligonucleotide-treated mice relative tomice treated with PBS. The mean % o of remaining SCAP mRNA in liversamples of mice treated with the GaXC™-SCAP oligonucleotide controlrelative to mice treated with PBS. Tables 6 to 8 show that a number ofthe GalXC™-SCAP oligonucleotides tested inhibit SCAP activity to agreater extent than the GaIXC™-SCAP oligonucleotide control.

TABLE 6 In Vivo Activity of GalXC ™-SCAP Oligonucleotides in Mice(single-dose, SQ, 2 mg/kg; 96-hr harvest; HDI of hSCAP plasmid in mice).GalXC ™- Oligo Animal SCAP 1 2 3 4 5 Average SEM PBS 70.0 125.3 145.259.4 — 100.0 20.9 20 120.7 88.7 89.0 90.6 67.1 91.2 8.6 27 47.7 58.452.6 45.9 63.5 53.6 3.3 33 — 95.8 — 71.8 72.5 80.0 7.9 42 67.8 70.5 50.779.1 26.7 58.9 9.3 43 62.4 46.8 50.2 72.9 90.0 64.5 7.9 44 50.6 108.540.0 42.0 79.5 64.1 13.2 57 54.0 — — 89.2 41.1 61.4 14.4 65 76.6 98.339.1 105.1 168.8 97.6 21.2 66 35.7 30.8 26.1 37.5 55.1 37.0 4.9 70 —12.6 30.8 11.2 5.83* 18.2 6.3 104 53.7 45.8 73.7 54.0 48.3 55.1 4.9 10523.7 101.6 50.3 62.9 100.6 67.8 15.0 106 59.6 29.8 28.4 53.5 30.5 40.46.7 107 30.3 12.4 43.0 13.1 22.1 24.2 5.7 108 35.5 71.6 46.4 54.2 48.151.1 5.9 113 50.5 55.2 85.0 38.8 42.9 54.5 8.1 117 58.7 82.1 63.0 46.951.6 60.4 6.1 120 54.1 — 43.7 55.7 90.5 61.0 10.2

TABLE 7 In Vivo Activity of GalXC ™-SCAP Oligonucleotides in Mice(single-dose, SQ, 2 mg/kg; 96-hr harvest; HDI of hSCAP plasmid in mice).GalXC ™- Oligo Animal SCAP 1 2 3 4 5 Average SEM PBS 105.9 122.9 90.2105.6 75.4 100.0 8.0 2 32.8 67.0 37.1 57.0 55.7 49.9 6.5 13 44.4 38.966.1 77.2 56.4 56.6 7.0 67 36.9 — 32.1 41.5 43.5 38.5 2.5 69 56.5 51.950.1 60.5 51.3 54.0 1.9 108 45.7 88.3 80.2 56.6 134.9 81.1 15.5 110 65.750.3 24.3 30.4 48.3 43.8 7.4 115 15.0 45.4 — 45.3 32.7 34.6 7.2 133 17.021.9 31.6 52.8 25.6 29.8 6.2 144 66.5 93.9 28.0 88.0 32.1 61.7 13.7 15721.4 22.9 72.8 14.1 43.3 34.9 10.6 159 24.6 45.3 58.0 30.4 34.9 38.6 5.9163 9.0 40.3 48.8 20.8 24.0 28.6 7.1 164 34.7 68.5 81.0 61.8 55.0 60.27.7 165 48.5 32.3 49.2 44.6 39.2 42.8 3.2 166 31.8 29.4 55.4 66.0 70.050.5 8.5 176 31.3 32.1 31.6 60.5 30.9 37.3 5.8 177 26.7 22.8 19.7 17.915.3 20.5 2.0

TABLE 8 In Vivo Activity of GalXC ™-SCAP Oligonucleotides in Mice(single-dose, SQ, 2 mg/kg; 96-hr harvest; HDI of hSCAP plasmid in mice).GalXC ™- Oligo Animal SCAP 1 2 3 4 5 Average SEM PBS 121.8 102.2 82.857.4 135.8 100.0 13.9 66 45.5 33.4 36.9 55.5 38.9 42.0 3.9 70 20.0 27.642.6 24.4 45.3 32.0 5.1 107 26.3 12.3 18.7 10.5 18.5 17.3 2.8 151 132.967.9 83.6 98.1 126.3 101.8 12.4 152 61.4 70.6 100.5 76.0 66.1 74.9 6.8153 89.8 68.2 54.4 128.9 69.7 82.2 13.0 154 117.0 114.8 124.6 39.4 167.8112.7 20.7 155 109.6 128.6 61.2 120.9 62.1 96.5 14.5 156 66.2 46.3 58.486.0 81.5 67.7 7.3 157 41.6 39.6 34.5 54.1 36.0 41.2 3.5

The tables above show that the in vivo HDI results are consistent withthe in vitro data in the Huh7 cells and 3D human spheroids of Example 3.

Based on the results above, 7 GaIXC™-SCAP oligonucleotides are selectedfor a dose-response study in the HDI mouse model, the results of whichare shown in Table 9.

TABLE 9 Dose-Response of GalXC ™-SCAP Oligonucleotides in Mice (GalXC ™multiple- dose, 0.3-3.0 mg/kg, 96-hr harvest; HDI of hSCAP plasmid inmice). Dose Animal (mg/kg) 1 2 3 4 5 Avg SEM Study 1 GalXC ™- PBS —113.3 106.6 93.6 119.7 66.8 100.0 9.4 SCAP — 82.1 85.1 46.0 57.5 36.761.5 9.6 Oligo — 60.6 27.9 36.1 35.4 — 53.3 14.4 70 0.3 18.8 5.3 10.018.3 12.4 13.0 2.6 1.0 62.5 67.9 43.5 — — 58.0 7.4 3.0 20.4 29.4 22.429.9 26.9 25.8 1.9 107 0.3 8.6 9.8 16.4 9.3 6.1 10.0 1.7 1.0 106.3 101.1121.0 70.0 61.4 92.0 11.3 3.0 1.1 47.7 36.2 69.0 57.7 42.3 11.7 133 0.319.7 16.6 20.1 23.3 18.6 19.6 1.1 1.0 75.7 39.3 44.1 79.7 71.3 62.0 8.43.0 32.7 19.6 44.6 33.4 62.2 38.5 7.1 177 0.3 15.1 15.7 8.2 27.4 32.719.8 4.5 1.0 113.3 106.6 93.6 119.7 66.8 100.0 9.4 3.0 82.1 85.1 46.057.5 36.7 61.5 9.6 Study 2 PBS — 60.6 83.1 141.2 40.6 174.4 100.0 25.1 —65.1 36.4 70.9 100.7 81.7 71.0 10.6 — 46.5 40.4 33.5 18.8 59.2 39.7 6.766 0.3 17.8 9.0 30.6 29.2 24.3 22.2 4.0 1.0 66.9 32.9 48.7 54.1 51.650.8 5.5 3.0 21.2 78.9 42.3 65.8 40.7 49.8 10.2 157 0.3 7.4 18.7 14.920.2 14.6 15.2 2.2 1.0 101.5 59.7 53.6 110.9 117.5 88.6 13.3 3.0 21.227.4 39.6 45.2 48.3 36.3 5.2 163 0.3 31.1 13.7 26.3 20.2 47.2 27.7 5.71.0 60.6 83.1 141.2 40.6 174.4 100.0 25.1 3.0 65.1 36.4 70.9 100.7 81.771.0 10.6

The GalXC™-SCAP oligonucleotides show a dose-dependent reduction ofhuman SCAP mRNA expression. The GalXC™-SCAP oligonucleotides have anED₅₀ between 0.4-0.8 mg/kg against exogenously expressed human SCAPmRNA.

Primate (NHP) studies: Based on the mouse results above, 6 GalXC™-SCAPoligonucleotides are selected for evaluation of their ability to inhibitSCAP activity in NHPs (e.g., rhesus macaques; Macaca mulatta) for asingle-dose (2 or 6 mg/kg), 84-day study. Here, the NHPs are grouped sothat their mean body weights (about 5.4 kg) are comparable between thecontrol and experimental groups. Each cohort contains 6 individuals (3male and 3 female individuals). The GalXC™-SCAP oligonucleotides areadministered SQ on Study Day 0. Blood samples are collected at 2pre-dose time points (i.e., Days −21 and 0) and then weekly after dosingfor a liver enzyme panel and lipid profile. Ultrasound-guided coreneedle liver biopsies are collected on Study Days −21, 28, 56, and 83.At each time point, total RNA derived from the liver biopsy samples isindividualed to qRT-PCR analysis to measure SCAP mRNA inoligonucleotide-treated monkeys relative to monkeys treated with acomparable volume of PBS. To normalize the data, the measurements aremade relative to the geometric mean of two reference genes, PPIB and 18SrRNA. As shown in Table 10, treating NHPs with the GalXC™-SCAPoligonucleotides inhibits SCAP activity in the liver, as determined by areduced amount of SCAP mRNA in liver samples fromoligonucleotide-treated NHPs relative to NHPs treated with PBS. For alltime points evaluated, GalXC™-SCAP oligonucleotides inhibit SCAPactivity to a greater extent than the benchmark PBS and time-matchedcontrols.

TABLE 10 SCAP mRNA Knockdown by Select GalXC ™-SCAP Oligonucleotides inNHP Liver (at Day 28 vs. Pre-Dose and Time-Matched PBS). Dose Animal(mg/kg) 1 2 3 4 5 6 Avg SEM GalXC ™- PBS — 158.8 91.4 79.9 91.3 91.487.3 100.0 11.9 SCAP 66 6.0 41.4 63.2 38.5 67.1 39.1 55.0 50.7 5.2 Oligo70 6.0 36.6 29.7 33.6 23.9 26.2 27.4 29.6 1.9 107 2.0 44.0 62.1 50.052.4 42.0 72.5 53.8 4.7 107 6.0 43.8 50.2 56.4 27.9 37.6 12.0 38.0 6.6157 6.0 55.7 55.0 39.5 41.9 19.3 42.0 42.2 5.4 163 6.0 24.6 29.1 32.926.6 45.6 37.3 32.7 3.2 177 6.0 42.7 49.2 33.7 38.3 23.6 50.4 39.7 4.1

TABLE 11 SCAP mRNA Knockdown by Select GalXC ™-SCAP Oligonucleotides inNHP Liver (at Day 56 vs. Pre-Dose and Time-Matched PBS). Dose Animal(mg/kg) 1 2 3 4 5 6 Avg SEM GalXC ™- PBS — 186.6 67.8 97.7 89.3 62.096.6 100.0 18.4 SCAP 66 6.0 58.6 76.4 57.2 42.2 40.8 71.0 57.7 5.9 Oligo70 6.0 43.5 28.1 23.5 37.5 39.9 30.1 33.8 3.1 107 2.0 40.6 69.1 48.974.2 39.7 77.2 58.3 7.0 107 6.0 37.4 72.7 68.1 29.9 68.3 42.8 53.2 7.6157 6.0 54.8 88.6 50.3 30.0 47.8 57.7 54.9 7.8 163 6.0 36.1 42.9 36.029.1 74.3 36.3 42.5 6.6 177 6.0 56.7 55.5 37.4 42.5 38.9 52.1 47.2 3.5

TABLE 12 SCAP mRNA Knockdown by Select GalXC ™-SCAP Oligonucleotides inNHP Liver (at Day 84 vs. Pre-Dose and Time-Matched PBS). Dose Animal(mg/kg) 1 2 3 4 5 6 Avg SEM GalXC ™- PBS — 126.5 101.8 106.6 136.9 32.296.1 100.0 15.0 SCAP 66 6.0 62.4 82.5 125.0 79.5 88.2 57.5 82.5 9.8Oligo 70 6.0 48.1 44.4 71.9 75.0 109.1 58.6 67.9 9.7 107 2.0 110.6 97.2109.1 86.0 136.8 87.4 104.5 7.7 107 6.0 75.2 90.7 165.7 49.7 125.3 60.594.5 17.9 157 6.0 36.2 88.4 95.2 79.8 83.4 104.1 81.2 9.7 163 6.0 39.772.3 40.3 14.8 81.1 89.2 56.2 11.8 177 6.0 42.1 80.8 103.4 96.5 94.5106.1 87.2 9.7

An about 70% reduction of SCAP mRNA is achieved after a single 6 mg/kgdose of GalXC™-SCAP oligonucleotide nos. 70 and 163, an about 60%reduction of SCAP mRNA is achieved after a single 6 mg/kg dose ofGalXC-SCAP oligonucleotide nos. 107, 157 and 177, and an about 50%reduction of SCAP mRNA is achieved after a single 6 mg/kg dose ofGalXC™-SCAP oligonucleotide no. 66. Moreover, a dose response isobserved following the 2 mg/kg and 6 mg/kg dose of GaIXC™-SCAPoligonucleotide no. 107, where the ED₅₀ is about 2 mg/kg. Likewise, asustained reduction of liver SCAP mRNA expression is observed 56 dayspost a single 6.0 mg/kg dose of the GalXC™-SCAP oligonucleotides. Anabout 50% reduction of SCAP mRNA is observed 84 days after a single doseof GalXC™-SCAP oligonucleotide nos. 70 and 163.

Taken together, these results show that GalXC™-SCAP oligonucleotidesdesigned to target human and NHP SCAP mRNA inhibit SCAP activity in vivo(as determined by the reduction of the amount of SCAP mRNA in treatedanimals).

SEQUENCES

The following nucleic and/or amino acid sequences are referred to in thedisclosure and are provided below for reference.

SEQ ID NO: 1-wild-type human SCAP (4254 bp; NCBI Ref. Seq. No. NM_012235.4)gggcacccggcggccaggagagagagggagggogccacgcaccggactgcgggccgagagcgcgcacgccgcgctccgcccctgctgccgcccccgtcgccgccgccgccgccgccgcagcttgggaggtgctgccaccacaggtacctgcacatgttgttctttgtcagtgctgtcaagtgtgtgccagggtgatccatggtcactttccgggatggcagcaaggtgacttcggctgaggatgaccctgactgaaaggctgcgtgagaagatatctcgggccttctacaaccatgggctcctctgtgcatcctatcccatccccatcatcctcttcacagggttctgcatcttagcctgctgctacccactgctgaaactccccttgccaggaacaggacctgtggaattcaccacccctgtgaaggattactcgcccccacctgtggactctgaccgcaaacaaggagagcctactgagcagcctgagtggtatgtgggtgccccggtggcttatgtccagcagatatttgtgaagtcctcagtgtttccctggcacaagaacctcctggcagtagatgtatttcgttcacctttgtcccgggcattccaactggtggaggagatccggaaccacgtgctgagagacagctctgggatcaggagcttggaggagttgtgtctgcaagtgaccgacctgctgccaggccttaggaagctcaggaacctactccctgagcatggatgcctgctgctgtcccctgggaacttctggcagaatgactgggaacgcttccatgctgatcctgacatcattgggaccatccaccagcacgagcctaaaaccctgcagacttcagccacactcaaagacttgttatttggtgttcctgggaagtacagcggggtgagcctctacaccaggaagaggatggtctcctacaccatcaccctggtcttccagcactaccatgccaagttcctgggcagcctgcgtgcccgcctgatgcttctgcaccccagccccaactgcagccttcgggcggagagcctggtccacgtgcacttcaaggaggagattggtgtcgctgagctcatcccccttgtgaccacctacatcatcttgtttgcctacatctacttctccacgcggaagatcgacatggtcaagtccaagtgggggctggccctggctgccgtggtcacagtgctcagctcgctgctcatgtctgtgggactctgcacactcttcggcctgacgcccaccctcaatggcggcgagattttcccctaccttgtggtggttattgggttagagaatgtgttggtgctcaccaagtctgtggtctcaaccccggtagacctggaggtgaagctgcggatcgcccaaggcctaagcagcgagagctggtccatcatgaagaacatggccacggagctgggcatcatcctcatcggctacttcaccctagtgcccgccatccaggagttctgtctctttgctgtcgtggggctggtgtctgacttcttccttcagatgctgtttttcaccactgtcctgtccattgacattcgccggatggagctagcagacctgaacaagcgactgccccctgaggcctgcctgccctcagccaagccagtgggacagccaacgcgctacgagcggcagctggctgtgaggccgtccacaccccacaccatcacgttgcagccgtcttccttccgaaacctgcggctccccaagaggctgcgtgttgtctacttcctggcccgcacccgcctggcacagcgcctcatcatggctggcaccgttgtctggattggcatcctggtatacacagacccagcagggctgcgcaactacctcgctgcccaggtgacggaacagagcccattgggtgagggagccctggctcccatgcccgtgcctagtggcatgctgccccccagccacccggaccctgccttctccatcttcccacctgatgcccctaagctacctgagaaccagacgtcgccaggcgagtcacctgagcgtggaggtccagcagaggttgtccatgacagcccagtcccagaggtaacctgggggcctgaggatgaggaactttggaggaaattgtccttccgccactggccgacgctcttcagctattacaacatcacactggccaagaggtacatcagcctgctgcccgtcatcccagtcacgctccgcctgaacccgagggaggctctggagggccggcaccctcaggacggccgcagtgcctggcccccaccggggcccatacctgctgggcactgggaagcaggacccaagggcccaggtggggtgcaggcccatggagacgtcacgctgtacaaggtggcggcgctgggcctggccaccggcatcgtcttggtgctgctgctgctctgcctctaccgcgtgctatgcccgcgcaactacgggcagctgggtggtgggcccgggggcggaggcgcggggagctgccctgcgacgactacggctatgcgccacccgagacggagatcgtgccgcttgtgctgcgcggccacctcatggacatcgagtgcctggccagcgacggcatgctgctggtgagctgctgcctggcaggccacgtctgcgtgtgggacgcgcagaccggggattgcctaacgcgcattccgcgcccaggcaggcagcgccgggacagtggcgtgggcagcgggcttgaggctcaggagagctgggaacgactttcagatggtgggaaggctggtccagaggagcctggggacagccctcccctgagacaccgcccccggggccctccgccgccttccctcttcggggaccagcctgacctcacctgcttaattgacaccaacttttcagcgcagcctcggtcctcacagcccactcagcccgagccccggcaccgggggtctgtggccgctctcgggactccccaggctatgacttcagctgcctggtgcagcgggtgtaccaggaggaggggctggcggccgtctgcacaccagccctgcgcccaccctcgcctgggccggtgctgtcccaggcccctgaggacgagggtggctcccccgagaaaggctccccttccctcgcctgggcccccagtgccgagggttccatctggagcttggagctgcagggcaacctcatcgtggtggggcggagcagcggccggctggaggtgtgggacgccattgaaggggtgctgtgctgcagcagcgaggaggtctcctcaggcattaccgctctggtgttcttggacaaaaggattgtggctgcacggctcaacggttcccttgatttcttctccttggagacccacactgccctcagccccctgcagtttagagggaccccagggcggggcagttcccctgcctctccagtgtacagcagcagcgacacagtggcctgtcacctgacccacacagtgccctgtgcacaccaaaaacccatcacagccctgaaagccgctgctgggcgcttggtgactgggagccaagaccacacactgagagtgttccgtctggaggactcgtgctgcctcttcacccttcagggccactcaggggccatcacgaccgtgtacattgaccagaccatggtgctggccagtggaggacaagatggggccatctgcctgtgggatgtactgactggcagccgggtcagccatgtgtttgctcaccgtggggatgtcacctcccttacctgtaccacctcctgtgtcatcagcagtggcctggatgacctcatcagcatctgggaccgcagcacaggcatcaagttctactccattcagcaggacctgggctgtggtgcaagcttgggtgtcatctcagacaacctgctggtgactggcggccagggctgtgtctccttttgggacctaaactacggggacctgttacagacagtctacctggggaagaacagtgaggcccagcctgcccgccagatcctggtgctggacaacgctgccattgtctgcaactttggcagtgagctcagcctggtgtatgtgccctctgtgctggagaagctggactgagcgcagggcctccttgcccaggcaggaggctggggtgctgtgtgggggccaatgcactgaacctggacttgggggaaagagccgagtatcttccagccgctgcctcctgactgtaataatattaaacttttttaaaaaaccatatcatcatctgtcaggcactttgggagctaSEQ ID NO: 2-wild-type human SCAP (1279 aa; NCBI Ref. Seq. No. NP_036367.2)MTLTERLREKISRAFYNHGLLCASYPIPHILFTGFCILACCYPLLKLPLPGTGPVEFTTPVKDYSPPPVDSDRKQGEPTEQPEWYVGAPVAYVQQIFVKSSVFPWHKNLLAVDVFRSPLSRAFQLVEEIRNHVLRDSSGIRSLEELCLQVTDLLPGLRKLRNLLPEHGCLLLSPGNFWQNDWERFHADPDIIGTIHQHEPKTLQTSATLKDLLFGVPGKYSGVSLYTRKRMVSYTITLVFQHYHAKFLGSLRARLMLLHPSPNCSLRAESLVHVHFKEEIGVAELIPLVTTYIILFAYIYFSTRKIDMVKSKWGLALAAVVTVLSSLLMSVGLCTLFGLTPTLNGGEIFPYLVVVIGLENVLVLTKSVVSTPVDLEVKLRIAQGLSSESWSIMKNMATELGIILIGYFTLVPAIQEFCLFAVVGLVSDFFLQMLFFTTVLSIDIRRMELADLNKRLPPEACLPSAKPVGQPTRYERQLAVRPSTPHTITLQPSSFRNLRLPKRLRVVYFLARTRLAQRLIMAGTVVWIGILVYTDPAGLRNYLAAQVTEQSPLGEGALAPMPVPSGMLPPSHPDPAFSIFPPDAPKLPENQTSPGESPERGGPAEVVHDSPVPEVTWGPEDEELWRKLSFRHWPTLFSYYNITLAKRYISLLPVIPVTLRLNPREALEGRHPQDGRSAWPPPGPIPAGHWEAGPKGPGGVQAHGDVTLYKVAALGLATGIVLVLLLLCLYRVLCPRNYGQLGGGPGRRRRGELPCDDYGYAPPETEIVPLVLRGHLMDIECLASDGMLLVSCCLAGHVCVWDAQTGDCLTRIPRPGRQRRDSGVGSGLEAQESWERLSDGGKAGPEEPGDSPPLRHRPRGPPPPSLFGDQPDLTCLIDTNFSAQPRSSQPTQPEPRHRAVCGRSRDSPGYDFSCLVQRVYQEEGLAAVCTPALRPPSPGPVLSQAPEDEGGSPEKGSPSLAWAPSAEGSIWSLELQGNLIVVGRSSGRLEVWDAIEGVLCCSSEEVSSGITALVFLDKRIVAARLNGSLDFFSLETHTALSPLQFRGTPGRGSSPASPVYSSSDTVACHLTHTVPCAHQKPITALKAAAGRLVTGSQDHTLRVFRLEDSCCLFTLQGHSGAITTVYIDQTMVLASGGQDGAICLWDVLTGSRVSHVFAHRGDVTSLTCTTSCVISSGLDDLISIWDRSTGIKFYSIQQDLGCGASLGVISDNLLVTGGQGCVSFWDLNYGDLLQTVYLGKNSEAQPARQILVLDNAAIVCNFGSELSLVYVPSVL EKLDSEQ ID NO: 3-wild-type mouse SCAP (4226 bp; NCBI Ref. Seq. No.NM_001001144.3)gttgagaggtgaaggggggggagctgcgcgggcgccgggggccgggagggagaggggggctccaaacaccggaccgcgggccaggagcgcgcaggccgttctccgccgctcggtcgccgccgcccgggagctgcctcgctgccacaggtgcctgcagatgatgtctgctgtaagtgatatccagcatcttccgggctgatccatggtcactttccgggatggcaacaaggtgacttagccgaggatgaccctgactgaaaggcttcgtgagaagatatctcaggccttctacaaccatgggctgctctgcgcatcctatccaattcccatcatcctcttcacaggactctgcatcttagcctgctgctacccgctgctgaagctccccttgcctggaacgggacctgtggaattctccacgcctgtgaagggttactcgcccccgcctgcggactctgaccacaaacaaggagagcccagcgagcagccagagtggtatgtgggtgcccccgtggcgtacatccaacagatatttgtgaagtcatcggtgtctccctggcacagaaatcttctggcagtcgatgtgttccggtcacctctgtcccgagcattccaactggtggaagagatccggaaccatgtgctgagagacagctcagggaccaagagcctggaggaggtttgcctgcaggtgacagacctgctgccaggcctcaggaaactccggagcctacttcccgaacatggctgcctgctgctgtcccctgggaacttctggcagaatgattgggagagattccatgccgaccctgacatcattgggaccatccatcaacatgagcccaaaactctacagacatcagccacactcaaagacttgctgtttggtgttcctgggaagtacagtggggtgagcctctacacaaggaaaaggatggtctcctacaccatcaccctggtcttccagcgctaccatgccaagtttctgagcagcctacgtgcccggctcatgctgctgcaccccagccccaactgcagcctccgagcagagaacctggtccacgtccacttcaaagaggagattggcattgctgagctcatcccgctcgtgaccacctacatcatcctgtttgcctacatctacttctccacacgcaagatcgacatggtcaagtccaagtggggcctcgccctggcagccgtggtcacagtacttagctcactgctcatgtctgtggggctctgcaccctcttcggcctgacgcccacactcaatggcggtgagatcttcccatacctggtggtcgttattgggctagagaacgtgttggtgctcaccaagtcagtggtatcaactccagtggacctcgaggtgaagcttcggattgcacaaggcttgagtagtgagagctggtccatcatgaagaacgcggcgaccgagctgggcatcatcctcattggctacttcaccctcgtgcctgctatccaggagttctgcctctttgctgttgtgggcctggtgtctgacttcttcctccagatgctgttcttcaccactgtcctgtcgatcgacattcgccggatggagctagcagacctaaacaagcggctgccccctgaatcctgcctgccctcagccaagcccgtggggaggccagcacgatatgagagacagcaggctgtacggccatccacgccacacaccatcacattgcaaccatcttccttccgaaacctgcggcttcccaaaaggctgcgtgtcatctacttcctggcccgcactcgcctggcccagcgcctcatcatggctggtaccgttgtctggattggcatcctggtatacaccgacccggcagggctgcgcacctaccttgctgcccaggtgacagagcagagcccactgggtgagggttccctgggccccatgcctgtgcctagcggagtgctgcctgccagccacccggaccctgcattctccatcttcccacctgatgctcctaaactgccagagaaccagaccttgccaggtgagctgcctgagcatgctggtccagcagagggtgtccatgacagccgagccccagaggtaacttgggggcctgaggatgaggagctgtggaggaaattgtccttccgccactggcccacactcttcaactactacaacatcacactggccaaaaggtacatcagcctgctgcctgtcatccctgtcacactacacctgaatccacgggaggctctggaggggcgacaccctcaggatggtcgcagtgcctgggccccacaagagcctttgcccgctggcctctgggagtccggacctaagggaccaggtggaacacagacccatggcgacattaccttgtacaaggtggccgcgcttggcctagcagcgggcatcgtcctggtgctgctgctgctctgcctctaccgggtgctctgcccgcgtaattatgggcagccgggtggtggccccggcaggcggaggcgcggggagctgccctgcgatgactacggctacgcaccgcccgagacggagatagtgccgctggtgctgcgaggtcacctcatggacatcgagtgtctggctagcgatgggatgctactagtgagctgctgcctggcaggccaagtctgcgtgtgggacgctcagacaggggactgcctcacacggatcccacgcccagggccacgccgggatagctgcggaggtggagcttttgagactcaggagaactgggaaaggctgtcagatggaggcaaggctagcccggaagaacctggagacagccctccgctgcgacgacgcccccgagggcctccaccgccttccctctttggggaccagcccgacctcacctgcttaatcgacaccaacttctcggtgcagctgcccccagagcccactcagcccgagcctcggcaccgggtgggctgtggccgctctagagactcgggttatgacttcagccgcctggtgcagcgtgtgtaccaggaggaaggcctggctgctatgcgcatgccggccctgcgcccaccctcccctggacctcccttgccccaggcctctcaagaagaggggactgcacctgagaagggctcccctcccctggcctggacccccagcacagccggttccatctggagcttagagctgcaaggcaatctcatcgtggttgggcggagcagcggccggctggaggtgtgggacgccattgagggggtgctctgctgcagcaatgaggagatctcctcaggcatcacagcccttgtcttcttggacaggaggattgtagctgctcggcttaatggttcccttgatttcttttctttggagacccacacttccctcagccccctgcagttcagagggaccccagggcgaggcagttctccttcctcatctgtgtacagcagcagcaacacagtgacctgtcatcggacccacacagtgccctgtgcacaccagaagcccatcacagccctgagagctgctgccgggcgcctagtgacagggagccaagaccatactctaagagtcttccgactggatgactcgtgttgcctctttaccctgaagggccactcaggggcaatcacagctgtgtacattgatcagaccatggtactggccagtggaggacaagatggagccatctgcctgtgggatgtactaacaggcagccgggtcagccaaacatttgctcaccgtggagatgttacctccctcacctgtaccgcttcctgtgtcattagtagtggcctggatgacttcatcagtatctgggaccgcagcacaggcatcaagctgtactccattcagcaggacctgggctgtggtgcaagcttgggtgtcatctcagataaccttctggtgaccggcggccagggctgtgtctccttttgggacctaaactatggggacctgttacagacagtctacttgggcaagaacagtgaagcccagcctgcccggcagattttggtgttggacaatgctgccattgtctgcaactttggcagtgagctcagcctagtgtatgtgccctctgtgctggagaaactggactgaaggcaggtcaagtacgctattccctttcccccatcccaaggtggggcacaggggatagcaactctttggacctagactagaggcaatagctgactctgaactgttgtctcctgactgtaataataaacttttttaaaaaaccacattt SEQ ID NO: 4-wild-type mouse SCAP (1276 aa; NCBI Ref. Seq. No.NP_001001144.2)MTLTERLREKISQAFYNHGLLCASYPIPIILFTGLCILACCYPLLKLPLPGTGPVEFSTPVKGYSPPPADSDHKQGEPSEQPEWYVGAPVAYIQQIFVKSSVSPWHRNLLAVDVFRSPLSRAFQLVEEIRNHVLRDSSGTKSLEEVCLQVTDLLPGLRKLRSLLPEHGCLLLSPGNFWQNDWERFHADPDIIGTIHQHEPKTLQTSATLKDLLFGVPGKYSGVSLYTRKRMVSYTITLVFQRYHAKFLSSLRARLMLLHPSPNCSLRAENLVHVHFKEEIGIAELIPLVTTYIILFAYIYFSTRKIDMVKSKWGLALAAVVTVLSSLLMSVGLCTLFGLTPTLNGGEIFPYLVVVIGLENVLVLTKSVVSTPVDLEVKLRIAQGLSSESWSIMKNAATELGIILIGYFTLVPAIQEFCLFAVVGLVSDFFLQMLFFTTVLSIDIRRMELADLNKRLPPESCLPSAKPVGRPARYERQQAVRPSTPHTITLQPSSFRNLRLPKRLRVIYFLARTRLAQRLIMAGTVVWIGILVYTDPAGLRTYLAAQVTEQSPLGEGSLGPMPVPSGVLPASHPDPAFSIFPPDAPKLPENQTLPGELPEHAGPAEGVHDSRAPEVTWGPEDEELWRKLSFRHWPTLFNYYNITLAKRYISLLPVIPVTLHLNPREALEGRHPQDGRSAWAPQEPLPAGLWESGPKGPGGTQTHGDITLYKVAALGLAAGIVLVLLLLCLYRVLCPRNYGQPGGGPGRRRRGELPCDDYGYAPPETEIVPLVLRGHLMDIECLASDGMLLVSCCLAGQVCVWDAQTGDCLTRIPRPGPRRDSCGGGAFETQENWERLSDGGKASPEEPGDSPPLRRRPRGPPPPSLFGDQPDLTCLIDTNFSVQLPPEPTQPEPRHRVGCGRSRDSGYDFSRLVQRVYQEEGLAAMRMPALRPPSPGPPLPQASQEEGTAPEKGSPPLAWTPSTAGSIWSLELQGNLIVVGRSSGRLEVWDAIEGVLCCSNEEISSGITALVFLDRRIVAARLNGSLDFFSLETHTSLSPLQFRGTPGRGSSPSSSVYSSSNTVTCHRTHTVPCAHQKPITALRAAAGRLVTGSQDHTLRVFRLDDSCCLFTLKGHSGAITAVYIDQTMVLASGGQDGAICLWDVLTGSRVSQTFAHRGDVTSLTCTASCVISSGLDDFISIWDRSTGIKLYSIQQDLGCGASLGVISDNLLVTGGQGCVSFWDLNYGDLLQTVYLGKNSEAQPARQILVLDNAAIVCNFGSELSLVYVPSVLEKL DSEQ ID NO: 5-wild-type rat SCAP (4281 bp; NCBI Ref. Seq. No. NM_001100966.2)gaaggggggggagctgcgcgggcgccgggcggccgggagggagaggggggctcgaaacaccggatcgcgggccaggagcgcgcaggccgctctccgccgctccgtcgccgccgcccgggagctgcctcgccgccacaggcacctctcccgtggttggaggaaacgaggcattctagaaggggatagcaggtacctgcagatgatgtgcattgtcattggtatccagcatcttccaggctgatccatggtcactttccgggatggcaacaaggtgacttagctgaggatgaccctgactgaaaggcttcgtgagaagatatctcaggcgttctacaaccatgggctgctctgcgcatcctaccccattcccatcatcctcttcacaggactctgcatcctagcctgctgctacccgctgctgaagcttcccttgcctggaacgggacccgtggaattctccacgcctgtgaagggttactcgcccccgcctgcggactctgaccacaaacaaggagagcccagtgagcagccagagtggtatgtgggtgcccccgtggcatacatccagcagatattcgtgaagtcatcagtgtctccctggcacagaaaccttctggcagtagatgtgttccggtcacctctgtcccgagcattccaactggtggaagagatccggaaccatgtgctgagagacagctcagggaccaagagcctggaggaagtttgcctgcaggtgacagacctgctgccaggcctcaggaaactccggagcctacttcccgaacatggctgcctgctgctgtcacctgggaacttctggcagaatgactgggaaagattccatgctgaccctgacatcattggaaccatccatcagcatgagcctaaaaccctacagacatcagccacactcaaagacttgctgttcggtgttcctgggaagtacagtggggtcagcctctacacgaggaagaggatggtctcatacaccatcaccctggtcttccagcgctaccatgccaagtttctgagcagcctccgtgcccggctcatgcttctgcaccccagccccaactgcagcctccgagcagagaacctggtgcatgtgcacttcaaagaggagattggcattgccgagctcatccccctcgtgaccacctacatcatcctgtttgcctacatctacttctccacacgcaagatcgacatggtcaagtccaagtggggcctcgccctggcagccgtggtcacagtgcttagctcgctgctcatgtctgtggggctctgcactctcttcggcctgacgcccacactcaatggcggcgagattttcccatatctggtggtggttattgggctagagaatgtgttggtgctcaccaagtcagtggtatcaactccagtggaccttgaggtgaagcttcgaattgcacaaggcttaagcagtgagagctggtccatcatgaagaacgtagcaactgaactgggcatcatcctcattggctacttcacccttgtgcctgccatccaagagttctgcctctttgctgtggtgggcctggtgtctgacttcttcctccagatgctgttcttcaccaccgtgctgtccatcgacattcgccggatggagctagcagacctgaacaagcggctgccccctgagtcctgcctgccctcagccaagcctgtggggaggccagcccgatatgagagacagctagctgtacggccgtccacaccacacaccatcacattgcaaccatcttccttccgaaacctgcggcttcccaaaaggctgcgtgtcatctacttcctggcccgcactcgcctggcacagcgcctcatcatggctggtacagttgtctggattggcatcctggtatatacagacccggcagggctgcgcacctacctcgctgcccaggtgacagaacagagcccactgggtgagggttccctggggcccatgcctgtgcctagtggagtgctgcctgccagccacccggaccctgccttctccatcttcccacctgatgctcctaaactgccagagaaccagacgttgccaggtgagctgcctgagcatgccgttccagcagagggcgtccaggacagccgagccccagaggtgacttgggggcccgaggatgaggagctgtggaggaaattgtccttccgccactggcccacactcttcaactactataatatcacactggccaaaaggtacatcagcctgctgcctgtcatccctgtcacactacacctgaatccacgggaggctctggaggggcgacaccctcaggatggccgcactgcctgggccccaccagagcctttgcctgctggcctgtgggagaccggacctaaggggccaggtggaacacagacccatggcgacattaccttgtacaaggtggctgcacttggcctggcagcgggcattgtcctagtgctgctgctgctctgcctctaccgggtgctctgcccgcgaaactacgggcagccgggtggtggtgcgggcaggcggaggcgcggagagctgccttgcgatgactatggctacgcaccgcctgagacggagatagtgccgctggtgctgcgagggcacctcatggacatcgagtgtctggctagcgatgggatgctcctggtgagctgctgcctggctggccaagtctgcgtgtgggatgcacagaccggggactgcctcactcgcatcccgcgccctgggccacgccgggacagctgcggaggcggagcttttgaagctcaggagaactgggaaagactgtctgatgggggcaaagctagcccggaagagcctggcgacagccctccgctgcgacgccgccctcgagggcctccaccgccttccctctttggggaccagccagacctcacctgcttaatcgacaccaacttctcagtgcagctgcccccagagcccactcagcccgagcctcggcaccgggcgggctgtggccgctctagagactctggttacgacttcagccgtctggtgcagcgtgtgtaccaagaggaaggcctggctgctgtgcacatgtcggccctgcgcccaccctccccgggacctcccctgccccaggcctctcaagaagaggggactgctcccgagaagggctccccccctctggcctgggcccccagcacagccggttccatctggagcttagagttgcaaggcagtctcatcgtggttgggcgaagcagcggccggctggaggtgtgggatgccattgagggcgtgctctgctgcagcaatgaggagatctcctcaggcatcacagcccttgtcttcttagagaccccagggagaggcagttctccttcctcgcctgtgtacagcagcagcaacactgtggcctgtcacctgacccacacagtcccctgtgcacaccagaaacccatcacagccctgagagcagcagcggggcgcctggtgacagggagccaagaccatactctgagagtcttccgactggaggattcgtgttgcctctttaccctgcagggccactcgggggcaatcacaactgtgtacattgatcagaccatggtattggccagtggaggacaagatggagccatctgcctgtgggatgtactaacaggcagccgggtcagccatacatttgctcaccgtggagatgtcacctccctcacctgtaccacttcctgtgttatcagtagtggcctggatgacttcatcaacatctgggaccgaagcacaggcatcaagctgtactccattcagcaggacctgggctgtggtgcaagcttgggtgtcatctctgataaccttctggtgaccggcggccagggatgtgtctccttttgggacctaaactatggggacctgttacagacagtctacttgggaaagaacagtgaagcccagcctgcccggcagattttggtgctggacaatgctgccattgtctgcaactttggcagtgagctcagcctagtgtatgtgccctctgtgctggagaaactggactgaaggcaggtcaactgcactatgcctttcccccatcccaaggtggggcactggggattgcaactctttggacctagactggaggcaataggtaggcatctttgcagctgactcagaactgttgtctcctgactgtaataataaacttttttttaaaaaaccacaSEQ ID NO: 6-wild-type rat SCAP (1276 aa; NCBI Ref. Seq. No. NP_001094436.1)MTLTERLREKISQAFYNHGLLCASYPIPIILFTGLCILACCYPLLKLPLPGTGPVEFSTPVKGYSPPPADSDHKQGEPSEQPEWYVGAPVAYIQQIFVKSSVSPWHRNLLAVDVFRSPLSRAFQLVEEIRNHVLRDSSGTKSLEEVCLQVTDLLPGLRKLRSLLPEHGCLLLSPGNFWQNDWERFHADPDIIGTIHQHEPKTLQTSATLKDLLFGVPGKYSGVSLYTRKRMVSYTITLVFQRYHAKFLSSLRARLMLLHPSPNCSLRAENLVHVHFKEEIGIAELIPLVTTYIILFAYIYFSTRKIDMVKSKWGLALAAVVTVLSSLLMSVGLCTLFGLTPTLNGGEIFPYLVVVIGLENVLVLTKSVVSTPVDLEVKLRIAQGLSSESWSIMKNVATELGIILIGYFTLVPAIQEFCLFAVVGLVSDFFLQMLFFTTVLSIDIRRMELADLNKRLPPESCLPSAKPVGRPARYERQLAVRPSTPHTITLQPSSFRNLRLPKRLRVIYFLARTRLAQRLIMAGTVVWIGILVYTDPAGLRTYLAAQVTEQSPLGEGSLGPMPVPSGVLPASHPDPAFSIFPPDAPKLPENQTLPGELPEHAVPAEGVQDSRAPEVTWGPEDEELWRKLSFRHWPTLFNYYNITLAKRYISLLPVIPVTLHLNPREALEGRHPQDGRTAWAPPEPLPAGLWETGPKGPGGTQTHGDITLYKVAALGLAAGIVLVLLLLCLYRVLCPRNYGQPGGGAGRRRRGELPCDDYGYAPPETEIVPLVLRGHLMDIECLASDGMLLVSCCLAGQVCVWDAQTGDCLTRIPRPGPRRDSCGGGAFEAQENWERLSDGGKASPEEPGDSPPLRRRPRGPPPPSLFGDQPDLTCLIDTNFSVQLPPEPTQPEPRHRAGCGRSRDSGYDFSRLVQRVYQEEGLAAVHMSALRPPSPGPPLPQASQEEGTAPEKGSPPLAWAPSTAGSIWSLELQGSLIVVGRSSGRLEVWDAIEGVLCCSNEEISSGITALVFLDRRIVAARLNGSLDFFSLETHTSLSPLQFRGTPGRGSSPSSPVYSSSNTVACHLTHTVPCAHQKPITALRAAAGRLVTGSQDHTLRVFRLEDSCCLFTLQGHSGAITTVYIDQTMVLASGGQDGAICLWDVLTGSRVSHTFAHRGDVTSLTCTTSCVISSGLDDFINIWDRSTGIKLYSIQQDLGCGASLGVISDNLLVTGGQGCVSFWDLNYGDLLQTVYLGKNSEAQPARQILVLDNAAIVCNFGSELSLVYVPSVLEKLDSEQ ID NO: 7-wild-type non-human primate SCAP (4135 bp; NCBI Ref. Seq. No.XM_001100342)agggagagagagagagagtgtgtgtgtgtgtgagtgtgtgtgtgtattttggaattgatgtcactagaacttacatacaggcattctgaaaccattccccagccacataactatcgcctccctccagcagccctagtgtgcagagccaagtactctttgttaactggcttttctcccttctgaccaggtacctgcacatgttgttctttgtcagtgccgtcaagtgtgtgccagggtgatccatggtcactttccgggatggcagcaaggtgacttcggctgaggatgaccctgactgaaaggctgcgtgagaagatatctcgggccttctacaaccatgggctcctctgtgcatcgtatcccatccccatcatcctcttcacggggttctgcatcttagcctgctgctacccactgctgaaactccccttgccaggaacaggacctgtggaattcaccacccctgtaaaggattactcgcccccgcctgtggactctgaccgcaaacaaggagagcctacggagcagcctgagtggtatgtgggtgccccggtggcttacgtccagcagatatttgtgaaatcctcagtgtttccctggcacaagaacctcctggcagtagatgtatttcgttcacctttgtcccgggcattccaactggtggaggagatccggaaccacgtgctgagagacagctctgggaccaggagcttggaggagttgtgtctgcaagtgaccgacctgctgccaggcctcaggaagctcagggacctactccctgagcatggatgcctgctgctgtcccctgggaatttctggcagaatgaccgggaacgcttccatgctgatcctgacatcattgggaccatccaccagcacgagcctaaaaccctgcagacttcagccacactcaaagacttgttgtttggtgttcccgggaagtacagcggggtgagcctctacaccaggaagaggatggtctcctacaccatcaccctggtcttccagcgctaccatgccaagttcctgggcagcctgcgtgcccgcctgatgcttctgcaccccagccccaactgcagccttcgggcggagagcctggtccacgtgcacttcaaggaggagattggtgtcgctgagctcatcccccttgtgaccacctacatcatcttgtttgcctacatctacttctccacgcggaagatcgacatggtcaagtccaagtgggggctggccctggccgccgtggtcacagtgctcagctcgctgctcatgtctgtgggactctgcacactcttcggcctgacgcccaccctcaatggcggcgagattttcccctaccttgtggtggttattgggttagagaatgtgttggtgctcaccaagtccgtggtctcaaccccggtagacctggaggtgaagctgcggatcgcccaaggcctaagcagcgagagctggtccatcatgaagaacatggccacggagctgggcatcatcctcattggctacttcaccctagtgcctgccatccaggagttctgtctctttgctgtcgtggggctggtgtctgacttcttccttcagatgctgtttttcaccactgtcctgtccattgacattcgccggatggagctagcggacctgaacaagcggctgccccctgaggcctgcctaccctcagccaagccagtggggcagccaacgcgctacgagcggcagctggctgtgcggccgtccacaccccacaccatcacgttgcagccgtcttccttccgaaacctgcggctccccaagaggctgcgtgttgtctacttcctggcccgcacccgcctggcacagcgtctcatcatggctggcaccgttgtctggattggcatcctggtatacacagacccagcagggctgcgcacctacctcgctgcccaggtgacggaacagagcccgctgggtgagggagccctggctcccatgcccgtgcctagtggcatgctgcccgccagccacccggaccctgccttctccatcttcccacctgatgcccctaagctacctgagaaccagacatcgccaggcgagccacctgagcatggaggtccagcagaggttgtccatgacagcccagtcccagaggtaacctgggggcctgaggatgaggaactttggaggaaattgtccttccgccactggccgacgctcttcagctattacaacatcacgctggccaagaggtacatcagcctgctgcctgtcatcccagtcacactccgcctgaacccgagggaggccctggagggccggcaccctcaggatggccgcagtgcctggcccccaccggggcccatacctgctgggcactgggaagcgggacccaagggcccaggtggggtgcaggcccatggagacgtcacactgtacaaggtggcgnnnnnnnnnnnnnnnnttgtgccgctggtcctgcgcggccacctcatggatatcgagtgcctggccagcgacggcatgctgctggtgagctgttgcctggcaggccacgtctgtgtgtgggacgcacagaccggggattgcctcacgcgtatcccgcgcccagggcagcgccgggacagtggcgtgggcagcgggcttgaggctcaggagagctgggaacgactttcagatggtgggaaggctggcccagaggagcctggggacagccctcccctgagacaccgcccccgggaccctccaccgccttccctcttcggggaccagcctgacctcacctgcttaattgacaccaacttttcggcgcagccacagccctcacagcccactcagcctgagccccggcaccgggcggtctgtggccgcgctcgggactccctaggctatgacttcagccgcctggtgcagcgcgtgtaccaggaggaggggctggcggccgtctgcacaccagccctgcgcccaccctcgcctgggccggtgctgccccaggcccctgaggacgagggtggctcccctgagaaaggctccccttcccttgcctgggcccccagtgcggagggttccatctggagcttggagctgcagggccacctcatcgtggtggggcggagcagcggccggctggaggtgtgggacgccattgaaggggtgctgtgctgcagcagcgaggaggtctcctcaggcattaccgctctggtcttcttggacaaaaggattgtggctgcgcggctcaacggttcccttgatttcttctccttggagacccacactgccctcagccccctgcagtttagagggaccccggggcagggcagttcccctgcctctccagtgtacggcagcagtgacacagtggcctgtcgcctgacccacacagtgccctgtgcacaccaaaaacccatcacagccctgaaagccgctgccgggcgcttggtgactgggagtcaagaccacacgctgagagtattccgtctggaggactcgtgctgcctcttcacccttcagggccactcgggggccatcacgactgtgtacattgaccagaccatggtgctggccagtggaggacaagatggggccatctgcctgtgggatgtactgactggcagccgggtcagccacatgtttgctcaccgtggggatgtcacctccctcacctgtaccacctcctgtgtcatcagcagtggcctggatgacctcatcagcatctgggaccgcagcacaggcatcaagttctactccattcagcaggatctgggctgtggtgcaagcttgggtgtcatctcagacaacctgctggtgaccggcggccaaggctgtgtctccttttgggacctaaactacggggacctgttacagacagtctacctggggaagaacagtgaggcccagcctgcccgccagatcctggtgctggacaacgctgccattgtctgcaactttggcagtgagctcagcctggtgtatgtgccctccgtgctggagaagctggactgagcatggggcctccctgcccaggcaggggtctggggtgctgtgtgggggccaatgcactgaacctggacttgggggaaagagccgagtatcttccagccgctgcctcctgactgtaatattaaacttttttaaaaaaccacatctgtcaggcactttgggaSEQ ID NO: 8-wild-type non-human primate SCAP (1229 aa; NCBI Ref. Seq. No.XP_001100342.2)MTLTERLREKISRAFYNHGLLCASYPIPIILFTGFCILACCYPLLKLPLPGTGPVEFTTPVKDYSPPPVDSDRKQGEPTEQPEWYVGAPVAYVQQIFVKSSVFPWHKNLLAVDVFRSPLSRAFQLVEEIRNHVLRDSSGTRSLEELCLQVTDLLPGLRKLRDLLPEHGCLLLSPGNFWQNDRERFHADPDIIGTIHQHEPKTLQTSATLKDLLFGVPGKYSGVSLYTRKRMVSYTITLVFQRYHAKFLGSLRARLMLLHPSPNCSLRAESLVHVHFKEEIGVAELIPLVTTYIILFAYIYFSTRKIDMVKSKWGLALAAVVTVLSSLLMSVGLCTLFGLTPTLNGGEIFPYLVVVIGLENVLVLTKSVVSTPVDLEVKLRIAQGLSSESWSIMKNMATELGIILIGYFTLVPAIQEFCLFAVVGLVSDFFLQMLFFTTVLSIDIRRMELADLNKRLPPEACLPSAKPVGQPTRYERQLAVRPSTPHTITLQPSSFRNLRLPKRLRVVYFLARTRLAQRLIMAGTVVWIGILVYTDPAGLRTYLAAQVTEQSPLGEGALAPMPVPSGMLPASHPDPAFSIFPPDAPKLPENQTSPGEPPEHGGPAEVVHDSPVPEVTWGPEDEELWRKLSFRHWPTLFSYYNITLAKRYISLLPVIPVTLRLNPREALEGRHPQDGRSAWPPPGPIPAGHWEAGPKGPGGVQAHGDVTLYKVAXXXXXXVPLVLRGHLMDIECLASDGMLLVSCCLAGHVCVWDAQTGDCLTRIPRPGQRRDSGVGSGLEAQESWERLSDGGKAGPEEPGDSPPLRHRPRDPPPPSLFGDQPDLTCLIDTNFSAQPQPSQPTQPEPRHRAVCGRARDSLGYDFSRLVQRVYQEEGLAAVCTPALRPPSPGPVLPQAPEDEGGSPEKGSPSLAWAPSAEGSIWSLELQGHLIVVGRSSGRLEVWDAIEGVLCCSSEEVSSGITALVFLDKRIVAARLNGSLDFFSLETHTALSPLQFRGTPGQGSSPASPVYGSSDTVACRLTHTVPCAHQKPITALKAAAGRLVTGSQDHTLRVFRLEDSCCLFTLQGHSGAITTVYIDQTMVLASGGQDGAICLWDVLTGSRVSHMFAHRGDVTSLTCTTSCVISSGLDDLISIWDRSTGIKFYSIQQDLGCGASLGVISDNLLVTGGQGCVSFWDLNYGDLLQTVYLGKNSEAQPARQILVLDNAAIVCNFGSE LSLVYVPSVLEKLD

SEQ ID NOS: 9-392 - GalXC™-SCAP Oligonucleotides (unmodified) GalXC-Sense Strand SEQ SEQ SCAP (passenger; ID Antisense Strand ID Oligo36-mer) NO: (guide; 22-mer) NO: 1 UGUUUGCCUACAUC 9 UAAGUAGAUGUAGGCA 10UACUUAGCAGCCGA AACAGG AAGGCUGC 2 GUUUGCCUACAUCU 11 UGAAGUAGAUGUAGGC 12ACUUCAGCAGCCGA AAACGG AAGGCUGC 3 UUUGCCUACAUCUA 13 UAGAAGUAGAUGUAGG 14CUUCUAGCAGCCGA CAAAGG AAGGCUGC 4 GCCUACAUCUACUU 15 UUGGAGAAGUAGAUGU 16CUCCAAGCAGCCGA AGGCGG AAGGCUGC 5 AAGAUCGACAUGGU 17 UACUUGACCAUGUCGA 18CAAGUAGCAGCCGA UCUUGG AAGGCUGC 6 AGAUCGACAUGGUC 19 UGACUUGACCAUGUCG 20AAGUCAGCAGCCGA AUCUGG AAGGCUGC 7 AUCGACAUGGUCAA 21 UUGGACUUGACCAUGU 22GUCCAAGCAGCCGA CGAUGG AAGGCUGC 8 GUGUUGGUGCUCAC 23 UACUUGGUGAGCACCA 24CAAGUAGCAGCCGA ACACGG AAGGCUGC 9 UGUUGGUGCUCACC 25 UGACUUGGUGAGCACC 26AAGUCAGCAGCCGA AACAGG AAGGCUGC 10 GAGAGCUGGUCCAU 27 UUCAUGAUGGACCAGC 28CAUGAAGCAGCCGA UCUCGG AAGGCUGC 11 AGAGCUGGUCCAUC 29 UUUCAUGAUGGACCAG 30AUGAAAGCAGCCGA CUCUGG AAGGCUGC 12 GAGCUGGUCCAUCA 31 UCUUCAUGAUGGACCA 32UGAAGAGCAGCCGA GCUCGG AAGGCUGC 13 AGCUGGUCCAUCAU 33 UUCUUCAUGAUGGACC 34GAAGAAGCAGCCGA AGCUGG AAGGCUGC 14 GCUGGUCCAUCAUG 35 UUUCUUCAUGAUGGAC 36AAGAAAGCAGCCGA CAGCGG AAGGCUGC 15 CUGGUCCAUCAUGA 37 UGUUCUUCAUGAUGGA 38AGAACAGCAGCCGA CCAGGG AAGGCUGC 16 CCGUUGUCUGGAUU 39 UAUGCCAAUCCAGACA 40GGCAUAGCAGCCGA ACGGGG AAGGCUGC 17 UUGUCUGGAUUGGC 41 UAGGAUGCCAAUCCAG 42AUCCUAGCAGCCGA ACAAGG AAGGCUGC 18 UGUCUGGAUUGGCA 43 UCAGGAUGCCAAUCCA 44UCCUGAGCAGCCGA GACAGG AAGGCUGC 19 GUCUGGAUUGGCAU 45 UCCAGGAUGCCAAUCC 46CCUGGAGCAGCCGA AGACGG AAGGCUGC 20 CUGGAUUGGCAUCC 47 UUACCAGGAUGCCAAU 48UGGUAAGCAGCCGA CCAGGG AAGGCUGC 21 UGGAUUGGCAUCCU 49 UAUACCAGGAUGCCAA 50GGUAUAGCAGCCGA UCCAGG AAGGCUGC 22 GGAUUGGCAUCCUG 51 UUAUACCAGGAUGCCA 52GUAUAAGCAGCCGA AUCCGG AAGGCUGC 23 GAUUGGCAUCCUGG 53 UGUAUACCAGGAUGCC 54UAUACAGCAGCCGA AAUCGG AAGGCUGC 24 AUUGGCAUCCUGGU 55 UUGUAUACCAGGAUGC 56AUACAAGCAGCCGA CAAUGG AAGGCUGC 25 CUCCAUCUUCCCAC 57 UAUCAGGUGGGAAGAU 58CUGAUAGCAGCCGA GGAGGG AAGGCUGC 26 CAUCUGCCUGUGGG 59 UUACAUCCCACAGGCA 60AUGUAAGCAGCCGA GAUGGG AAGGCUGC 27 UCUGCCUGUGGGAU 61 UAGUACAUCCCACAGG 62GUACUAGCAGCCGA CAGAGG AAGGCUGC 28 GUGGUGCAAGCUUG 63 UACACCCAAGCUUGCA 64GGUGUAGCAGCCGA CCACGG AAGGCUGC 29 UGGUGCAAGCUUGG 65 UGACACCCAAGCUUGC 66GUGUCAGCAGCCGA ACCAGG AAGGCUGC 30 GGUGCAAGCUUGGG 67 UUGACACCCAAGCUUG 68UGUCAAGCAGCCGA CACCGG AAGGCUGC 31 GUGCAAGCUUGGGU 69 UAUGACACCCAAGCUU 70GUCAUAGCAGCCGA GCACGG AAGGCUGC 32 GCAAGCUUGGGUGU 71 UAGAUGACACCCAAGC 72CAUCUAGCAGCCGA UUGCGG AAGGCUGC 33 CAAGCUUGGGUGUC 73 UGAGAUGACACCCAAG 74AUCUCAGCAGCCGA CUUGGG AAGGCUGC 34 AAGCUUGGGUGUCA 75 UUGAGAUGACACCCAA 76UCUCAAGCAGCCGA GCUUGG AAGGCUGC 35 AGCUUGGGUGUCAU 77 UCUGAGAUGACACCCA 78CUCAGAGCAGCCGA AGCUGG AAGGCUGC 36 GCUUGGGUGUCAUC 79 UUCUGAGAUGACACCC 80UCAGAAGCAGCCGA AAGCGG AAGGCUGC 37 GUGUCUCCUUUUGG 81 UAGGUCCCAAAAGGAG 82GACCUAGCAGCCGA ACACGG AAGGCUGC 38 UGUCUCCUUUUGGG 83 UUAGGUCCCAAAAGGA 84ACCUAAGCAGCCGA GACAGG AAGGCUGC 39 GGGGACCUGUUACA 85 UCUGUCUGUAACAGGU 86GACAGAGCAGCCGA CCCCGG AAGGCUGC 40 GGGACCUGUUACAG 87 UACUGUCUGUAACAGG 88ACAGUAGCAGCCGA UCCCGG AAGGCUGC 41 GGACCUGUUACAGA 89 UGACUGUCUGUAACAG 90CAGUCAGCAGCCGA GUCCGG AAGGCUGC 42 GACCUGUUACAGAC 91 UAGACUGUCUGUAACA 92AGUCUAGCAGCCGA GGUCGG AAGGCUGC 43 ACCUGUUACAGACA 93 UUAGACUGUCUGUAAC 94GUCUAAGCAGCCGA AGGUGG AAGGCUGC 44 UGCCAUUGUCUGCA 95 UAAAGUUGCAGACAAU 96ACUUUAGCAGCCGA GGCAGG AAGGCUGC 45 GCCAUUGUCUGCAA 97 UCAAAGUUGCAGACAA 98CUUUGAGCAGCCGA UGGCGG AAGGCUGC 46 CCAUUGUCUGCAAC 99 UCCAAAGUUGCAGACA 100UUUGGAGCAGCCGA AUGGGG AAGGCUGC 47 AUUGUCUGCAACUU 101 UUGCCAAAGUUGCAGA102 UGGCAAGCAGCCGA CAAUGG AAGGCUGC 48 UCUGCAACUUUGGC 103UUCACUGCCAAAGUUG 104 AGUGAAGCAGCCGA CAGAGG AAGGCUGC 49 CUACCCACUGCUGA105 UGAGUUUCAGCAGUGG 106 AACUCAGCAGCCGA GUAGGG AAGGCUGC 50GCCAGGAACAGGAC 107 UCACAGGUCCUGUUCC 108 CUGUGAGCAGCCGA UGGCGG AAGGCUGC51 GAACAGGACCUGUG 109 UAAUUCCACAGGUCCU 110 GAAUUAGCAGCCGA GUUCGGAAGGCUGC 52 ACAGGACCUGUGGA 111 UUGAAUUCCACAGGUC 112 AUUCAAGCAGCCGACUGUGG AAGGCUGC 53 UGGAAUUCACCACC 113 UACAGGGGUGGUGAAU 114CCUGUAGCAGCCGA UCCAGG AAGGCUGC 54 CUUGUGACCACCUA 115 UUGAUGUAGGUGGUCA116 CAUCAAGCAGCCGA CAAGGG AAGGCUGC 55 UUGUGACCACCUAC 117UAUGAUGUAGGUGGUC 118 AUCAUAGCAGCCGA ACAAGG AAGGCUGC 56 UGUGACCACCUACA119 UGAUGAUGUAGGUGGU 120 UCAUCAGCAGCCGA CACAGG AAGGCUGC 57GUGACCACCUACAU 121 UAGAUGAUGUAGGUGG 122 CAUCUAGCAGCCGA UCACGG AAGGCUGC58 UGACCACCUACAUC 123 UAAGAUGAUGUAGGUG 124 AUCUUAGCAGCCGA GUCAGGAAGGCUGC 59 GACCACCUACAUCA 125 UCAAGAUGAUGUAGGU 126 UCUUGAGCAGCCGAGGUCGG AAGGCUGC 60 ACCACCUACAUCAU 127 UACAAGAUGAUGUAGG 128CUUGUAGCAGCCGA UGGUGG AAGGCUGC 61 CCACCUACAUCAUC 129 UAACAAGAUGAUGUAG130 UUGUUAGCAGCCGA GUGGGG AAGGCUGC 62 CACCUACAUCAUCU 131UAAACAAGAUGAUGUA 132 UGUUUAGCAGCCGA GGUGGG AAGGCUGC 63 ACCUACAUCAUCUU133 UCAAACAAGAUGAUGU 134 GUUUGAGCAGCCGA AGGUGG AAGGCUGC 64CCUACAUCAUCUUG 135 UGCAAACAAGAUGAUG 136 UUUGCAGCAGCCGA UAGGGG AAGGCUGC65 CUACAUCAUCUUGU 137 UGGCAAACAAGAUGAU 138 UUGCCAGCAGCCGA GUAGGGAAGGCUGC 66 ACAUCAUCUUGUUU 139 UUAGGCAAACAAGAUG 140 GCCUAAGCAGCCGAAUGUGG AAGGCUGC 67 AUCAUCUUGUUUGC 141 UUGUAGGCAAACAAGA 142CUACAAGCAGCCGA UGAUGG AAGGCUGC 68 UCAUCUUGUUUGCC 143 UAUGUAGGCAAACAAG144 UACAUAGCAGCCGA AUGAGG AAGGCUGC 69 AUCUUGUUUGCCUA 145UAGAUGUAGGCAAACA 146 CAUCUAGCAGCCGA AGAUGG AAGGCUGC 70 UCUUGUUUGCCUAC147 UUAGAUGUAGGCAAAC 148 AUCUAAGCAGCCGA AAGAGG AAGGCUGC 71UUUCCCCUACCUUG 149 UCACCACAAGGUAGGG 150 UGGUGAGCAGCCGA GAAAGG AAGGCUGC72 UUCCCCUACCUUGU 151 UCCACCACAAGGUAGG 152 GGUGGAGCAGCCGA GGAAGGAAGGCUGC 73 CCCUACCUUGUGGU 153 UUAACCACCACAAGGU 154 GGUUAAGCAGCCGAAGGGGG AAGGCUGC 74 CUACCUUGUGGUGG 155 UAAUAACCACCACAAG 156UUAUUAGCAGCCGA GUAGGG AAGGCUGC 75 UACCUUGUGGUGGU 157 UCAAUAACCACCACAA158 UAUUGAGCAGCCGA GGUAGG AAGGCUGC 76 ACCUUGUGGUGGUU 159UCCAAUAACCACCACA 160 AUUGGAGCAGCCGA AGGUGG AAGGCUGC 77 CCUUGUGGUGGUUA161 UCCCAAUAACCACCACA 162 UUGGGAGCAGCCGA AGGGG AAGGCUGC 78 CUUGUGGUGGUUA163 UACCCAAUAACCACCAC 164 UUGGGUAGCAGCCG AAGGG AAAGGCUGC 79UUGUGGUGGUUAU 165 UAACCCAAUAACCACC 166 UGGGUUAGCAGCCG ACAAGG AAAGGCUGC80 UGUGGUGGUUAUU 167 UUAACCCAAUAACCAC 168 GGGUUAAGCAGCCG CACAGGAAAGGCUGC 81 GUGGUGGUUAUUG 169 UCUAACCCAAUAACCA 170 GGUUAGAGCAGCCGCCACGG AAAGGCUGC 82 UGGUGGUUAUUGG 171 UUCUAACCCAAUAACC 172GUUAGAAGCAGCCG ACCAGG AAAGGCUGC 83 GGUGGUUAUUGGG 173 UCUCUAACCCAAUAAC174 UUAGAGAGCAGCCG CACCGG AAAGGCUGC 84 GUGGUUAUUGGGU 175UUCUCUAACCCAAUAA 176 UAGAGAAGCAGCCG CCACGG AAAGGCUGC 85 UGGUUAUUGGGUU177 UUUCUCUAACCCAAUA 178 AGAGAAAGCAGCCG ACCAGG AAAGGCUGC 86GGUUAUUGGGUUA 179 UAUUCUCUAACCCAAU 180 GAGAAUAGCAGCCG AACCGG AAAGGCUGC87 GUUAUUGGGUUAG 181 UCAUUCUCUAACCCAA 182 AGAAUGAGCAGCCG UAACGGAAAGGCUGC 88 UUAUUGGGUUAGA 183 UACAUUCUCUAACCCA 184 GAAUGUAGCAGCCGAUAAGG AAAGGCUGC 89 AUUGGGUUAGAGA 185 UACACAUUCUCUAACC 186AUGUGUAGCAGCCG CAAUGG AAAGGCUGC 90 UUGGGUUAGAGAA 187 UAACACAUUCUCUAAC188 UGUGUUAGCAGCCG CCAAGG AAAGGCUGC 91 GGUUAGAGAAUGU 189UACCAACACAUUCUCU 190 GUUGGUAGCAGCCG AACCGG AAAGGCUGC 92 GUUAGAGAAUGUG191 UCACCAACACAUUCUC 192 UUGGUGAGCAGCCG UAACGG AAAGGCUGC 93UUAGAGAAUGUGU 193 UGCACCAACACAUUCU 194 UGGUGCAGCAGCCG CUAAGG AAAGGCUGC94 UAGAGAAUGUGUU 195 UAGCACCAACACAUUC 196 GGUGCUAGCAGCCG UCUAGGAAAGGCUGC 95 AGAGAAUGUGUUG 197 UGAGCACCAACACAUU 198 GUGCUCAGCAGCCGCUCUGG AAAGGCUGC 96 GAGAAUGUGUUGG 199 UUGAGCACCAACACAU 200UGCUCAAGCAGCCG UCUCGG AAAGGCUGC 97 AGAAUGUGUUGGU 201 UGUGAGCACCAACACA202 GCUCACAGCAGCCG UUCUGG AAAGGCUGC 98 AAUGUGUUGGUGC 203UUGGUGAGCACCAACA 204 UCACCAAGCAGCCG CAUUGG AAAGGCUGC 99 AUGUGUUGGUGCUC205 UUUGGUGAGCACCAAC 206 ACCAAAGCAGCCGA ACAUGG AAGGCUGC 100UGUGUUGGUGCUCA 207 UCUUGGUGAGCACCAA 208 CCAAGAGCAGCCGA CACAGG AAGGCUGC101 UGGUCCAUCAUGAA 209 UUGUUCUUCAUGAUGG 210 GAACAAGCAGCCGA ACCAGGAAGGCUGC 102 GGUCCAUCAUGAAG 211 UAUGUUCUUCAUGAUG 212 AACAUAGCAGCCGAGACCGG AAGGCUGC 103 CUGACUUCUUCCUU 213 UAUCUGAAGGAAGAAG 214CAGAUAGCAGCCGA UCAGGG AAGGCUGC 104 ACUUCUUCCUUCAG 215 UAGCAUCUGAAGGAAG216 AUGCUAGCAGCCGA AAGUGG AAGGCUGC 105 UCCUUCAGAUGCUG 217UAAAAACAGCAUCUGA 218 UUUUUAGCAGCCGA AGGAGG AAGGCUGC 106 CCUUCAGAUGCUGU219 UGAAAAACAGCAUCUG 220 UUUUCAGCAGCCGA AAGGGG AAGGCUGC 107CUUCAGAUGCUGUU 221 UUGAAAAACAGCAUCU 222 UUUCAAGCAGCCGA GAAGGG AAGGCUGC108 UUCAGAUGCUGUUU 223 UGUGAAAAACAGCAUC 224 UUCACAGCAGCCGA UGAAGGAAGGCUGC 109 CAGAUGCUGUUUUU 225 UUGGUGAAAAACAGCA 226 CACCAAGCAGCCGAUCUGGG AAGGCUGC 110 AGAUGCUGUUUUUC 227 UGUGGUGAAAAACAGC 228ACCACAGCAGCCGA AUCUGG AAGGCUGC 111 GAUGCUGUUUUUCA 229 UAGUGGUGAAAAACAG230 CCACUAGCAGCCGA CAUCGG AAGGCUGC 112 AUGCUGUUUUUCAC 231UCAGUGGUGAAAAACA 232 CACUGAGCAGCCGA GCAUGG AAGGCUGC 113 UGCUGUUUUUCACC233 UACAGUGGUGAAAAAC 234 ACUGUAGCAGCCGA AGCAGG AAGGCUGC 114GCUGUUUUUCACCA 235 UGACAGUGGUGAAAAA 236 CUGUCAGCAGCCGA CAGCGG AAGGCUGC115 UGUUUUUCACCACU 237 UAGGACAGUGGUGAAA 238 GUCCUAGCAGCCGA AACAGGAAGGCUGC 116 GUUUUUCACCACUG 239 UCAGGACAGUGGUGAA 240 UCCUGAGCAGCCGAAAACGG AAGGCUGC 117 UUUUUCACCACUGU 241 UACAGGACAGUGGUGA 242CCUGUAGCAGCCGA AAAAGG AAGGCUGC 118 UUUUCACCACUGUC 243 UGACAGGACAGUGGUG244 CUGUCAGCAGCCGA AAAAGG AAGGCUGC 119 UUCACCACUGUCCU 245UUGGACAGGACAGUGG 246 GUCCAAGCAGCCGA UGAAGG AAGGCUGC 120 CACCACUGUCCUGU247 UAAUGGACAGGACAGU 248 CCAUUAGCAGCCGA GGUGGG AAGGCUGC 121ACCACUGUCCUGUC 249 UCAAUGGACAGGACAG 250 CAUUGAGCAGCCGA UGGUGG AAGGCUGC122 CCACUGUCCUGUCC 251 UUCAAUGGACAGGACA 252 AUUGAAGCAGCCGA GUGGGGAAGGCUGC 123 CACUGUCCUGUCCA 253 UGUCAAUGGACAGGAC 254 UUGACAGCAGCCGAAGUGGG AAGGCUGC 124 ACUGUCCUGUCCAU 255 UUGUCAAUGGACAGGA 256UGACAAGCAGCCGA CAGUGG AAGGCUGC 125 CUAAGCUACCUGAG 257 UUGGUUCUCAGGUAGC258 AACCAAGCAGCCGA UUAGGG AAGGCUGC 126 GAGGUCCAGCAGAG 259UACAACCUCUGCUGGA 260 GUUGUAGCAGCCGA CCUCGG AAGGCUGC 127 GCAGAGGUUGUCCA261 UUGUCAUGGACAACCU 262 UGACAAGCAGCCGA CUGCGG AAGGCUGC 128CAGAGGUUGUCCAU 263 UCUGUCAUGGACAACC 264 GACAGAGCAGCCGA UCUGGG AAGGCUGC129 GAGGAUGAGGAAC 265 UUCCAAAGUUCCUCAU 266 UUUGGAAGCAGCCG CCUCGGAAAGGCUGC 130 GAACUUUGGAGGA 267 UACAAUUUCCUCCAAA 268 AAUUGUAGCAGCCGGUUCGG AAAGGCUGC 131 GACGCUCUUCAGCU 269 UGUAAUAGCUGAAGAG 270AUUACAGCAGCCGA CGUCGG AAGGCUGC 132 ACGCUCUUCAGCUA 271 UUGUAAUAGCUGAAGA272 UUACAAGCAGCCGA GCGUGG AAGGCUGC 133 CGCUCUUCAGCUAU 273UUUGUAAUAGCUGAAG 274 UACAAAGCAGCCGA AGCGGG AAGGCUGC 134 GCUCUUCAGCUAUU275 UGUUGUAAUAGCUGAA 276 ACAACAGCAGCCGA GAGCGG AAGGCUGC 135CUCUUCAGCUAUUA 277 UUGUUGUAAUAGCUGA 278 CAACAAGCAGCCGA AGAGGG AAGGCUGC136 UCUUCAGCUAUUAC 279 UAUGUUGUAAUAGCUG 280 AACAUAGCAGCCGA AAGAGGAAGGCUGC 137 CUUCAGCUAUUACA 281 UGAUGUUGUAAUAGCU 282 ACAUCAGCAGCCGAGAAGGG AAGGCUGC 138 UUCAGCUAUUACAA 283 UUGAUGUUGUAAUAGC 284CAUCAAGCAGCCGA UGAAGG AAGGCUGC 139 CCAGCCUGACCUCA 285 UGCAGGUGAGGUCAGG286 CCUGCAGCAGCCGA CUGGGG AAGGCUGC 140 CAGCCUGACCUCAC 287UAGCAGGUGAGGUCAG 288 CUGCUAGCAGCCGA GCUGGG AAGGCUGC 141 AGCCUGACCUCACC289 UAAGCAGGUGAGGUCA 290 UGCUUAGCAGCCGA GGCUGG AAGGCUGC 142GCCUGACCUCACCU 291 UUAAGCAGGUGAGGUC 292 GCUUAAGCAGCCGA AGGCGG AAGGCUGC143 CCUGACCUCACCUG 293 UUUAAGCAGGUGAGGU 294 CUUAAAGCAGCCGA CAGGGGAAGGCUGC 144 CUGACCUCACCUGC 295 UAUUAAGCAGGUGAGG 296 UUAAUAGCAGCCGAUCAGGG AAGGCUGC 145 UGACCUCACCUGCU 297 UAAUUAAGCAGGUGAG 298UAAUUAGCAGCCGA GUCAGG AAGGCUGC 146 GACCUCACCUGCUU 299 UCAAUUAAGCAGGUGA300 AAUUGAGCAGCCGA GGUCGG AAGGCUGC 147 ACCUCACCUGCUUA 301UUCAAUUAAGCAGGUG 302 AUUGAAGCAGCCGA AGGUGG AAGGCUGC 148 CCUCACCUGCUUAA303 UGUCAAUUAAGCAGGU 304 UUGACAGCAGCCGA GAGGGG AAGGCUGC 149CUCACCUGCUUAAU 305 UUGUCAAUUAAGCAGG 306 UGACAAGCAGCCGA UGAGGG AAGGCUGC150 UCACCUGCUUAAUU 307 UGUGUCAAUUAAGCAG 308 GACACAGCAGCCGA GUGAGGAAGGCUGC 151 CACCUGCUUAAUUG 309 UGGUGUCAAUUAAGCA 310 ACACCAGCAGCCGAGGUGGG AAGGCUGC 152 ACCUGCUUAAUUGA 311 UUGGUGUCAAUUAAGC 312CACCAAGCAGCCGA AGGUGG AAGGCUGC 153 CCUGCUUAAUUGAC 313 UUUGGUGUCAAUUAAG314 ACCAAAGCAGCCGA CAGGGG AAGGCUGC 154 CUGCUUAAUUGACA 315UGUUGGUGUCAAUUAA 316 CCAACAGCAGCCGA GCAGGG AAGGCUGC 155 UGCUUAAUUGACAC317 UAGUUGGUGUCAAUUA 318 CAACUAGCAGCCGA AGCAGG AAGGCUGC 156GCUUAAUUGACACC 319 UAAGUUGGUGUCAAUU 320 AACUUAGCAGCCGA AAGCGG AAGGCUGC157 CUUAAUUGACACCA 321 UAAAGUUGGUGUCAAU 322 ACUUUAGCAGCCGA UAAGGGAAGGCUGC 158 UUAAUUGACACCAA 323 UAAAAGUUGGUGUCAA 324 CUUUUAGCAGCCGAUUAAGG AAGGCUGC 159 UAAUUGACACCAAC 325 UGAAAAGUUGGUGUCA 326UUUUCAGCAGCCGA AUUAGG AAGGCUGC 160 AUUGAAGGGGUGC 327 UAGCACAGCACCCCUUC328 UGUGCUAGCAGCCG AAUGG AAAGGCUGC 161 CUUGGACAAAAGGA 329UCACAAUCCUUUUGUC 330 UUGUGAGCAGCCGA CAAGGG AAGGCUGC 162 UUGGACAAAAGGA331 UCCACAAUCCUUUUGU 332 UUGUGGAGCAGCCG CCAAGG AAAGGCUGC 163UCAACGGUUCCCUU 333 UAAAUCAAGGGAACCG 334 GAUUUAGCAGCCGA UUGAGG AAGGCUGC164 CAACGGUUCCCUUG 335 UGAAAUCAAGGGAACC 336 AUUUCAGCAGCCGA GUUGGGAAGGCUGC 165 AACGGUUCCCUUGA 337 UAGAAAUCAAGGGAAC 338 UUUCUAGCAGCCGACGUUGG AAGGCUGC 166 ACGGUUCCCUUGAU 339 UAAGAAAUCAAGGGAA 340UUCUUAGCAGCCGA CCGUGG AAGGCUGC 167 GUACAUUGACCAGA 341 UCAUGGUCUGGUCAAU342 CCAUGAGCAGCCGA GUACGG AAGGCUGC 168 ACCUGUACCACCUC 343UCACAGGAGGUGGUAC 344 CUGUGAGCAGCCGA AGGUGG AAGGCUGC 169 CCUGUACCACCUCC345 UACACAGGAGGUGGUA 346 UGUGUAGCAGCCGA CAGGGG AAGGCUGC 170GUACCACCUCCUGU 347 UAUGACACAGGAGGUG 348 GUCAUAGCAGCCGA GUACGG AAGGCUGC171 GCACAGGCAUCAAG 349 UUAGAACUUGAUGCCU 350 UUCUAAGCAGCCGA GUGCGGAAGGCUGC 172 ACAGGCAUCAAGUU 351 UAGUAGAACUUGAUGC 352 CUACUAGCAGCCGACUGUGG AAGGCUGC 173 CAGGCAUCAAGUUC 353 UGAGUAGAACUUGAUG 354UACUCAGCAGCCGA CCUGGG AAGGCUGC 174 AGGCAUCAAGUUCU 355 UGGAGUAGAACUUGAU356 ACUCCAGCAGCCGA GCCUGG AAGGCUGC 175 GGCAUCAAGUUCUA 357UUGGAGUAGAACUUGA 358 CUCCAAGCAGCCGA UGCCGG AAGGCUGC 176 GCAUCAAGUUCUAC359 UAUGGAGUAGAACUUG 360 UCCAUAGCAGCCGA AUGCGG AAGGCUGC 177CAUCAAGUUCUACU 361 UAAUGGAGUAGAACUU 362 CCAUUAGCAGCCGA GAUGGG AAGGCUGC178 AUCAAGUUCUACUC 363 UGAAUGGAGUAGAACU 364 CAUUCAGCAGCCGA UGAUGGAAGGCUGC 179 UCAAGUUCUACUCC 365 UUGAAUGGAGUAGAAC 366 AUUCAAGCAGCCGAUUGAGG AAGGCUGC 180 CAAGUUCUACUCCA 367 UCUGAAUGGAGUAGAA 368UUCAGAGCAGCCGA CUUGGG AAGGCUGC 181 AAGUUCUACUCCAU 369 UGCUGAAUGGAGUAGA370 UCAGCAGCAGCCGA ACUUGG AAGGCUGC 182 AGUUCUACUCCAUU 371UUGCUGAAUGGAGUAG 372 CAGCAAGCAGCCGA AACUGG AAGGCUGC 183 GUUCUACUCCAUUC373 UCUGCUGAAUGGAGUA 374 AGCAGAGCAGCCGA GAACGG AAGGCUGC 184GUGUCAUCUCAGAC 375 UAGGUUGUCUGAGAUG 376 AACCUAGCAGCCGA ACACGG AAGGCUGC185 CAUCUCAGACAACC 377 UCAGCAGGUUGUCUGA 378 UGCUGAGCAGCCGA GAUGGGAAGGCUGC 186 UCAGACAACCUGCU 379 UUCACCAGCAGGUUGU 380 GGUGAAGCAGCCGACUGAGG AAGGCUGC 187 CGGGGACCUGUUAC 381 UUGUCUGUAACAGGUC 382AGACAAGCAGCCGA CCCGGG AAGGCUGC 188 GACAACGCUGCCAU 383 UAGACAAUGGCAGCGU384 UGUCUAGCAGCCGA UGUCGG AAGGCUGC 189 GCUGCCUCCUGACU 385UAUUACAGUCAGGAGG 386 GUAAUAGCAGCCGA CAGCGG AAGGCUGC 190 CUGCCUCCUGACUG387 UUAUUACAGUCAGGAG 388 UAAUAAGCAGCCGA GCAGGG AAGGCUGC 191UAAUAUUAAACUU 389 UUUAAAAAAGUUUAAU 390 UUUUAAAGCAGCCG AUUAGG AAAGGCUGC192 AAUAUUAAACUUU 391 UUUUAAAAAAGUUUAA 392 UUUAAAAGCAGCCG UAUUGGAAAGGCUGC

SEQ ID NOs: 393-776 - GalXC ™-SCAP Oligonucleotides (modified) GalXC-SEQ SEQ SCAP Sense Strand ID Antisense Strand ID Oligo (passenger;36-mer) NO: (guide; 22-mer) NO: 1 mU*mGmUmUmUmGmC/ 393[MePhosphonate-4O- 394 i2FC//i2FU//i2FA//i2FC/mUs]/i2FA/*/i2FA/*/i2FG//i2FU/ mAmUmCmUmAmCmUmUmAmGmCmAmGmCmCmG[ademA-mA/i2FG/mAmU/i2FG/ GalNAc][ademA- mUmAmG/i2FG/ GalNAc][ademA-mCmAmAmAmCmA*mG*mG GalNAc]mGmGmCmUmGmC 2 mG*mUmUmUmGmCmC/ 395[MePhosphonate-4O- 396 i2FU//i2FA//i2FC//i2FA/mUs]/i2FG/*/i2FA/*/i2FA//i2FG/ mUmCmUmAmCmUmUmCmAmGmCmAmGmCmCmG[ademA-mU/i2FA/mGmA/i2FU/ GalNAc][ademA- mGmUmA/i2FG/ GalNAc][ademA-mGmCmAmAmAmC*mG*mG GalNAc]mGmGmCmUmGmC 3 mU*mUmUmGmCmCmU/ 397[MePhosphonate-4O- 398 i2FA//i2FC//i2FA//i2FU/mUs]/i2FA/*/i2FG/*/i2FA//i2FA/ mCmUmAmCmUmUmCmUmAmGmCmAmGmCmCmG[ademA-mG/i2FU/mAmG/i2FA/ GalNAc][ademA- mUmGmU/i2FA/ GalNAc][ademA-mGmGmCmAmAmA*mG*mG GalNAc]mGmGmCmUmGmC 4 mG*mCmCmUmAmCmA/ 399[MePhosphonate-4O- 400 i2FU//i2FC//i2FU//i2FA/mUs]/i2FU/*/i2FG/*/i2FG//i2FA/ mCmUmUmCmUmCmCmAmAmGmCmAmGmCmCmG[ademA-mG/i2FA/mAmG/i2FU/ GalNAc][ademA- mAmGmA/i2FU/ GalNAc][ademA-mGmUmAmGmGmC*mG*mG GalNAc]mGmGmCmUmGmC 5 mA*mAmGmAmUmCmG/ 401[MePhosphonate-4O- 402 i2FA//i2FC//i2FA//i2FU/mUs]/i2FA/*/i2FC/*/i2FU//i2FU/ mGmGmUmCmAmAmGmUmAmGmCmAmGmCmCmG[ademA-mG/i2FA/mCmC/i2FA/ GalNAc][ademA- mUmGmU/i2FC/mGmAmUmCmUmU*mG*mGGalNAc][ademA- GalNAc]mGmGmCmUmGmC 6 mA*mGmAmUmCmGmA/ 403[MePhosphonate-4O- 404 i2FC//i2FA//i2FU//i2FG/mUs]/i2FG/*/i2FA/*/i2FC//i2FU/ mGmUmCmAmAmGmUmCmAmGmCmAmGmCmCmG[ademA-mU/i2FG/mAmC/i2FC/ GalNAc][ademA- mAmUmG/i2FU/mCmGmAmUmCmU*mG*mGGalNAc][ademA- GalNAc]mGmGmCmUmGmC 7 mA*mUmCmGmAmCmA/ 405[MePhosphonate-4O- 406 i2FU//i2FG//i2FG//i2FU/mUs]/i2FU/*/i2FG/*/i2FG//i2FA/ mCmAmAmGmUmCmCmAmAmGmCmAmGmCmCmG[ademA-mC/i2FU/mUmG/i2FA/ GalNAc][ademA- mCmCmA/i2FU/ GalNAc][ademA-mGmUmCmGmAmU*mG*mG GalNAc]mGmGmCmUmGmC 8 mG*mUmGmUmUmGmG/ 407[MePhosphonate-4O- 408 i2FU//i2FG//i2FC//i2FU/mUs]/i2FA/*/i2FC/*/i2FU//i2FU/ mCmAmCmCmAmAmGmUmAmGmCmAmGmCmCmG[ademA-mG/i2FG/mUmG/i2FA/ GalNAc][ademA- mGmCmA/i2FC/ GalNAc][ademA-mCmAmAmCmAmC*mG*mG GalNAc]mGmGmCmUmGmC 9 mU*mGmUmUmGmGmU/ 409[MePhosphonate-4O- 410 i2FG//i2FC//i2FU//i2FC/mUs]/i2FG/*/i2FA/*/i2FC//i2FU/ mAmCmCmAmAmGmUmCmAmGmCmAmGmCmCmG[ademA-mU/i2FG/mGmU/i2FG/ GalNAc][ademA- mAmGmC/i2FA/ GalNAc][ademA-mCmCmAmAmCmA*mG*mG GalNAc]mGmGmCmUmGmC 10 mG*mAmGmAmGmCmU/ 411[MePhosphonate-4O- 412 i2FG//i2FG//i2FU//i2FC/mUs]/i2FU/*/i2FC/*/i2FA//i2FU/ mCmAmUmCmAmUmGmAmAmGmCmAmGmCmCmG[ademA-mG/i2FA/mUmG/i2FG/ GalNAc][ademA- mAmCmC/i2FA/ GalNAc][ademA-mGmCmUmCmUmC*mG*mG GalNAc]mGmGmCmUmGmC 11 mA*mGmAmGmCmUmG/ 413[MePhosphonate-4O- 414 i2FG//i2FU//i2FC//i2FC/mUs]/i2FU/*/i2FU/*/i2FC//i2FA/ mAmUmCmAmUmGmAmAmAmGmCmAmGmCmCmG[ademA-mU/i2FG/mAmU/i2FG/ GalNAc][ademA- mGmAmC/i2FC/ GalNAc][ademA-mAmGmCmUmCmU*mG*mG GalNAc]mGmGmCmUmGmC 12 mG*mAmGmCmUmGmG/ 415[MePhosphonate-4O- 416 i2FU//i2FC//i2FC//i2FA/mUs]/i2FC/*/i2FU/*/i2FU//i2FC/ 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SEQ ID NO: 777 Target Sequence 1 ACATCATCTTGTTTGCCTA SEQ ID NO: 778Target Sequence 2 TCTTGTTTGCCTACATCTA SEQ ID NO: 779 Target Sequence 3CTTCAGATGCTGTTTTTCA SEQ ID NO: 780 Target Sequence 4 CGCTCTTCAGCTATTACAASEQ ID NO: 781 Target Sequence 5 CTTAATTGACACCAACTTT SEQ ID NO: 782Target Sequence 6 TCAACGGTTCCCTTGATTT SEQ ID NO: 783 Target Sequence 7CATCAAGTTCTACTCCATT SEQ ID NO: 784 Artificial Sequence GCAGCCGAAAGGCUGC

SEQ ID NOs: 785-1168-SCAP Oligonucleotides Sense Strand SEQ SEQ SCAP(passenger; ID Antisense Strand ID Oligo 19-mer) NO: (guide; 19-mer) NO:1 UGUUUGCCUACAUC 785 AAGUAGAUGUAGGCAA 786 UACUU ACA 2 GUUUGCCUACAUCU 787GAAGUAGAUGUAGGCA 788 ACUUC AAC 3 UUUGCCUACAUCUA 789 AGAAGUAGAUGUAGGC 790CUUCU AAA 4 GCCUACAUCUACUU 791 UGGAGAAGUAGAUGUA 792 CUCCA GGC 5AAGAUCGACAUGGU 793 ACUUGACCAUGUCGAU 794 CAAGU CUU 6 AGAUCGACAUGGUC 795GACUUGACCAUGUCGA 796 AAGUC UCU 7 AUCGACAUGGUCAA 797 UGGACUUGACCAUGUC 798GUCCA GAU 8 GUGUUGGUGCUCAC 799 ACUUGGUGAGCACCAA 800 CAAGU CAC 9UGUUGGUGCUCACC 801 GACUUGGUGAGCACCA 802 AAGUC ACA 10 GAGAGCUGGUCCAU 803UCAUGAUGGACCAGCU 804 CAUGA CUC 11 AGAGCUGGUCCAUC 805 UUCAUGAUGGACCAGC806 AUGAA UCU 12 GAGCUGGUCCAUCA 807 CUUCAUGAUGGACCAG 808 UGAAG CUC 13AGCUGGUCCAUCAU 809 UCUUCAUGAUGGACCA 810 GAAGA GCU 14 GCUGGUCCAUCAUG 811UUCUUCAUGAUGGACC 812 AAGAA AGC 15 CUGGUCCAUCAUGA 813 GUUCUUCAUGAUGGAC814 AGAAC CAG 16 CCGUUGUCUGGAUU 815 AUGCCAAUCCAGACAA 816 GGCAU CGG 17UUGUCUGGAUUGGC 817 AGGAUGCCAAUCCAGA 818 AUCCU CAA 18 UGUCUGGAUUGGCA 819CAGGAUGCCAAUCCAG 820 UCCUG ACA 19 GUCUGGAUUGGCAU 821 CCAGGAUGCCAAUCCA822 CCUGG GAC 20 CUGGAUUGGCAUCC 823 UACCAGGAUGCCAAUC 824 UGGUA CAG 21UGGAUUGGCAUCCU 825 AUACCAGGAUGCCAAU 826 GGUAU CCA 22 GGAUUGGCAUCCUG 827UAUACCAGGAUGCCAA 828 GUAUA UCC 23 GAUUGGCAUCCUGG 829 GUAUACCAGGAUGCCA830 UAUAC AUC 24 AUUGGCAUCCUGGU 831 UGUAUACCAGGAUGCC 832 AUACA AAU 25CUCCAUCUUCCCAC 833 AUCAGGUGGGAAGAUG 834 CUGAU GAG 26 CAUCUGCCUGUGGG 835UACAUCCCACAGGCAG 836 AUGUA AUG 27 UCUGCCUGUGGGAU 837 AGUACAUCCCACAGGC838 GUACU AGA 28 GUGGUGCAAGCUUG 839 ACACCCAAGCUUGCACC 840 GGUGU AC 29UGGUGCAAGCUUGG 841 GACACCCAAGCUUGCA 842 GUGUC CCA 30 GGUGCAAGCUUGGG 843UGACACCCAAGCUUGC 844 UGUCA ACC 31 GUGCAAGCUUGGGU 845 AUGACACCCAAGCUUG846 GUCAU CAC 32 GCAAGCUUGGGUGU 847 AGAUGACACCCAAGCU 848 CAUCU UGC 33CAAGCUUGGGUGUC 849 GAGAUGACACCCAAGC 850 AUCUC UUG 34 AAGCUUGGGUGUCA 851UGAGAUGACACCCAAG 852 UCUCA CUU 35 AGCUUGGGUGUCAU 853 CUGAGAUGACACCCAA854 CUCAG GCU 36 GCUUGGGUGUCAUC 855 UCUGAGAUGACACCCA 856 UCAGA AGC 37GUGUCUCCUUUUGG 857 AGGUCCCAAAAGGAGA 858 GACCU CAC 38 UGUCUCCUUUUGGG 859UAGGUCCCAAAAGGAG 860 ACCUA ACA 39 GGGGACCUGUUACA 861 CUGUCUGUAACAGGUC862 GACAG CCC 40 GGGACCUGUUACAG 863 ACUGUCUGUAACAGGU 864 ACAGU CCC 41GGACCUGUUACAGA 865 GACUGUCUGUAACAGG 866 CAGUC UCC 42 GACCUGUUACAGAC 867AGACUGUCUGUAACAG 868 AGUCU GUC 43 ACCUGUUACAGACA 869 UAGACUGUCUGUAACA870 GUCUA GGU 44 UGCCAUUGUCUGCA 871 AAAGUUGCAGACAAUG 872 ACUUU GCA 45GCCAUUGUCUGCAA 873 CAAAGUUGCAGACAAU 874 CUUUG GGC 46 CCAUUGUCUGCAAC 875CCAAAGUUGCAGACAA 876 UUUGG UGG 47 AUUGUCUGCAACUU 877 UGCCAAAGUUGCAGAC878 UGGCA AAU 48 UCUGCAACUUUGGC 879 UCACUGCCAAAGUUGC 880 AGUGA AGA 49CUACCCACUGCUGA 881 GAGUUUCAGCAGUGGG 882 AACUC UAG 50 GCCAGGAACAGGAC 883CACAGGUCCUGUUCCU 884 CUGUG GGC 51 GAACAGGACCUGUG 885 AAUUCCACAGGUCCUG886 GAAUU UUC 52 ACAGGACCUGUGGA 887 UGAAUUCCACAGGUCC 888 AUUCA UGU 53UGGAAUUCACCACC 889 ACAGGGGUGGUGAAUU 890 CCUGU CCA 54 CUUGUGACCACCUA 891UGAUGUAGGUGGUCAC 892 CAUCA AAG 55 UUGUGACCACCUAC 893 AUGAUGUAGGUGGUCA894 AUCAU CAA 56 UGUGACCACCUACA 895 GAUGAUGUAGGUGGUC 896 UCAUC ACA 57GUGACCACCUACAU 897 AGAUGAUGUAGGUGGU 898 CAUCU CAC 58 UGACCACCUACAUC 899AAGAUGAUGUAGGUGG 900 AUCUU UCA 59 GACCACCUACAUCA 901 CAAGAUGAUGUAGGUG902 UCUUG GUC 60 ACCACCUACAUCAU 903 ACAAGAUGAUGUAGGU 904 CUUGU GGU 61CCACCUACAUCAUC 905 AACAAGAUGAUGUAGG 906 UUGUU UGG 62 CACCUACAUCAUCU 907AAACAAGAUGAUGUAG 908 UGUUU GUG 63 ACCUACAUCAUCUU 909 CAAACAAGAUGAUGUA910 GUUUG GGU 64 CCUACAUCAUCUUG 911 GCAAACAAGAUGAUGU 912 UUUGC AGG 65CUACAUCAUCUUGU 913 GGCAAACAAGAUGAUG 914 UUGCC UAG 66 ACAUCAUCUUGUUU 915UAGGCAAACAAGAUGA 916 GCCUA UGU 67 AUCAUCUUGUUUGC 917 UGUAGGCAAACAAGAU918 CUACA GAU 68 UCAUCUUGUUUGCC 919 AUGUAGGCAAACAAGA 920 UACAU UGA 69AUCUUGUUUGCCUA 921 AGAUGUAGGCAAACAA 922 CAUCU GAU 70 UCUUGUUUGCCUAC 923UAGAUGUAGGCAAACA 924 AUCUA AGA 71 UUUCCCCUACCUUG 925 CACCACAAGGUAGGGG926 UGGUG AAA 72 UUCCCCUACCUUGU 927 CCACCACAAGGUAGGG 928 GGUGG GAA 73CCCUACCUUGUGGU 929 UAACCACCACAAGGUA 930 GGUUA GGG 74 CUACCUUGUGGUGG 931AAUAACCACCACAAGG 932 UUAUU UAG 75 UACCUUGUGGUGGU 933 CAAUAACCACCACAAG934 UAUUG GUA 76 ACCUUGUGGUGGUU 935 CCAAUAACCACCACAA 936 AUUGG GGU 77CCUUGUGGUGGUUA 937 CCCAAUAACCACCACAA 938 UUGGG GG 78 CUUGUGGUGGUUA 939ACCCAAUAACCACCACA 940 UUGGGU AG 79 UUGUGGUGGUUAU 941 AACCCAAUAACCACCAC942 UGGGUU AA 80 UGUGGUGGUUAUU 943 UAACCCAAUAACCACC 944 GGGUUA ACA 81GUGGUGGUUAUUG 945 CUAACCCAAUAACCACC 946 GGUUAG AC 82 UGGUGGUUAUUGG 947UCUAACCCAAUAACCA 948 GUUAGA CCA 83 GGUGGUUAUUGGG 949 CUCUAACCCAAUAACC950 UUAGAG ACC 84 GUGGUUAUUGGGU 951 UCUCUAACCCAAUAAC 952 UAGAGA CAC 85UGGUUAUUGGGUU 953 UUCUCUAACCCAAUAA 954 AGAGAA CCA 86 GGUUAUUGGGUUA 955AUUCUCUAACCCAAUA 956 GAGAAU ACC 87 GUUAUUGGGUUAG 957 CAUUCUCUAACCCAAU958 AGAAUG AAC 88 UUAUUGGGUUAGA 959 ACAUUCUCUAACCCAA 960 GAAUGU UAA 89AUUGGGUUAGAGA 961 ACACAUUCUCUAACCC 962 AUGUGU AAU 90 UUGGGUUAGAGAA 963AACACAUUCUCUAACC 964 UGUGUU CAA 91 GGUUAGAGAAUGU 965 ACCAACACAUUCUCUA966 GUUGGU ACC 92 GUUAGAGAAUGUG 967 CACCAACACAUUCUCU 968 UUGGUG AAC 93UUAGAGAAUGUGU 969 GCACCAACACAUUCUC 970 UGGUGC UAA 94 UAGAGAAUGUGUU 971AGCACCAACACAUUCU 972 GGUGCU CUA 95 AGAGAAUGUGUUG 973 GAGCACCAACACAUUC974 GUGCUC UCU 96 GAGAAUGUGUUGG 975 UGAGCACCAACACAUU 976 UGCUCA CUC 97AGAAUGUGUUGGU 977 GUGAGCACCAACACAU 978 GCUCAC UCU 98 AAUGUGUUGGUGC 979UGGUGAGCACCAACAC 980 UCACCA AUU 99 AUGUGUUGGUGCUC 981 UUGGUGAGCACCAACA982 ACCAA CAU 100 UGUGUUGGUGCUCA 983 CUUGGUGAGCACCAAC 984 CCAAG ACA 101UGGUCCAUCAUGAA 985 UGUUCUUCAUGAUGGA 986 GAACA CCA 102 GGUCCAUCAUGAAG 987AUGUUCUUCAUGAUGG 988 AACAU ACC 103 CUGACUUCUUCCUU 989 AUCUGAAGGAAGAAGU990 CAGAU CAG 104 ACUUCUUCCUUCAG 991 AGCAUCUGAAGGAAGA 992 AUGCU AGU 105UCCUUCAGAUGCUG 993 AAAAACAGCAUCUGAA 994 UUUUU GGA 106 CCUUCAGAUGCUGU 995GAAAAACAGCAUCUGA 996 UUUUC AGG 107 CUUCAGAUGCUGUU 997 UGAAAAACAGCAUCUG998 UUUCA AAG 108 UUCAGAUGCUGUUU 999 GUGAAAAACAGCAUCU 1000 UUCAC GAA 109CAGAUGCUGUUUUU 1001 UGGUGAAAAACAGCAU 1002 CACCA CUG 110 AGAUGCUGUUUUUC1003 GUGGUGAAAAACAGCA 1004 ACCAC UCU 111 GAUGCUGUUUUUCA 1005AGUGGUGAAAAACAGC 1006 CCACU AUC 112 AUGCUGUUUUUCAC 1007 CAGUGGUGAAAAACAG1008 CACUG CAU 113 UGCUGUUUUUCACC 1009 ACAGUGGUGAAAAACA 1010 ACUGU GCA114 GCUGUUUUUCACCA 1011 GACAGUGGUGAAAAAC 1012 CUGUC AGC 115UGUUUUUCACCACU 1013 AGGACAGUGGUGAAAA 1014 GUCCU ACA 116 GUUUUUCACCACUG1015 CAGGACAGUGGUGAAA 1016 UCCUG AAC 117 UUUUUCACCACUGU 1017ACAGGACAGUGGUGAA 1018 CCUGU AAA 118 UUUUCACCACUGUC 1019 GACAGGACAGUGGUGA1020 CUGUC AAA 119 UUCACCACUGUCCU 1021 UGGACAGGACAGUGGU 1022 GUCCA GAA120 CACCACUGUCCUGU 1023 AAUGGACAGGACAGUG 1024 CCAUU GUG 121ACCACUGUCCUGUC 1025 CAAUGGACAGGACAGU 1026 CAUUG GGU 122 CCACUGUCCUGUCC1027 UCAAUGGACAGGACAG 1028 AUUGA UGG 123 CACUGUCCUGUCCA 1029GUCAAUGGACAGGACA 1030 UUGAC GUG 124 ACUGUCCUGUCCAU 1031 UGUCAAUGGACAGGAC1032 UGACA AGU 125 CUAAGCUACCUGAG 1033 UGGUUCUCAGGUAGCU 1034 AACCA UAG126 GAGGUCCAGCAGAG 1035 ACAACCUCUGCUGGAC 1036 GUUGU CUC 127GCAGAGGUUGUCCA 1037 UGUCAUGGACAACCUC 1038 UGACA UGC 128 CAGAGGUUGUCCAU1039 CUGUCAUGGACAACCU 1040 GACAG CUG 129 GAGGAUGAGGAAC 1041UCCAAAGUUCCUCAUC 1042 UUUGGA CUC 130 GAACUUUGGAGGA 1043 ACAAUUUCCUCCAAAG1044 AAUUGU UUC 131 GACGCUCUUCAGCU 1045 GUAAUAGCUGAAGAGC 1046 AUUAC GUC132 ACGCUCUUCAGCUA 1047 UGUAAUAGCUGAAGAG 1048 UUACA CGU 133CGCUCUUCAGCUAU 1049 UUGUAAUAGCUGAAGA 1050 UACAA GCG 134 GCUCUUCAGCUAUU1051 GUUGUAAUAGCUGAAG 1052 ACAAC AGC 135 CUCUUCAGCUAUUA 1053UGUUGUAAUAGCUGAA 1054 CAACA GAG 136 UCUUCAGCUAUUAC 1055 AUGUUGUAAUAGCUGA1056 AACAU AGA 137 CUUCAGCUAUUACA 1057 GAUGUUGUAAUAGCUG 1058 ACAUC AAG138 UUCAGCUAUUACAA 1059 UGAUGUUGUAAUAGCU 1060 CAUCA GAA 139CCAGCCUGACCUCA 1061 GCAGGUGAGGUCAGGC 1062 CCUGC UGG 140 CAGCCUGACCUCAC1063 AGCAGGUGAGGUCAGG 1064 CUGCU CUG 141 AGCCUGACCUCACC 1065AAGCAGGUGAGGUCAG 1066 UGCUU GCU 142 GCCUGACCUCACCU 1067 UAAGCAGGUGAGGUCA1068 GCUUA GGC 143 CCUGACCUCACCUG 1069 UUAAGCAGGUGAGGUC 1070 CUUAA AGG144 CUGACCUCACCUGC 1071 AUUAAGCAGGUGAGGU 1072 UUAAU CAG 145UGACCUCACCUGCU 1073 AAUUAAGCAGGUGAGG 1074 UAAUU UCA 146 GACCUCACCUGCUU1075 CAAUUAAGCAGGUGAG 1076 AAUUG GUC 147 ACCUCACCUGCUUA 1077UCAAUUAAGCAGGUGA 1078 AUUGA GGU 148 CCUCACCUGCUUAA 1079 GUCAAUUAAGCAGGUG1080 UUGAC AGG 149 CUCACCUGCUUAAU 1081 UGUCAAUUAAGCAGGU 1082 UGACA GAG150 UCACCUGCUUAAUU 1083 GUGUCAAUUAAGCAGG 1084 GACAC UGA 151CACCUGCUUAAUUG 1085 GGUGUCAAUUAAGCAG 1086 ACACC GUG 152 ACCUGCUUAAUUGA1087 UGGUGUCAAUUAAGCA 1088 CACCA GGU 153 CCUGCUUAAUUGAC 1089UUGGUGUCAAUUAAGC 1090 ACCAA AGG 154 CUGCUUAAUUGACA 1091 GUUGGUGUCAAUUAAG1092 CCAAC CAG 155 UGCUUAAUUGACAC 1093 AGUUGGUGUCAAUUAA 1094 CAACU GCA156 GCUUAAUUGACACC 1095 AAGUUGGUGUCAAUUA 1096 AACUU AGC 157CUUAAUUGACACCA 1097 AAAGUUGGUGUCAAUU 1098 ACUUU AAG 158 UUAAUUGACACCAA1099 AAAAGUUGGUGUCAAU 1100 CUUUU UAA 159 UAAUUGACACCAAC 1101GAAAAGUUGGUGUCAA 1102 UUUUC UUA 160 AUUGAAGGGGUGC 1103 AGCACAGCACCCCUUCA1104 UGUGCU AU 161 CUUGGACAAAAGGA 1105 CACAAUCCUUUUGUCC 1106 UUGUG AAG162 UUGGACAAAAGGA 1107 CCACAAUCCUUUUGUC 1108 UUGUGG CAA 163UCAACGGUUCCCUU 1109 AAAUCAAGGGAACCGU 1110 GAUUU UGA 164 CAACGGUUCCCUUG1111 GAAAUCAAGGGAACCG 1112 AUUUC UUG 165 AACGGUUCCCUUGA 1113AGAAAUCAAGGGAACC 1114 UUUCU GUU 166 ACGGUUCCCUUGAU 1115 AAGAAAUCAAGGGAAC1116 UUCUU CGU 167 GUACAUUGACCAGA 1117 CAUGGUCUGGUCAAUG 1118 CCAUG UAC168 ACCUGUACCACCUC 1119 CACAGGAGGUGGUACA 1120 CUGUG GGU 169CCUGUACCACCUCC 1121 ACACAGGAGGUGGUAC 1122 UGUGU AGG 170 GUACCACCUCCUGU1123 AUGACACAGGAGGUGG 1124 GUCAU UAC 171 GCACAGGCAUCAAG 1125UAGAACUUGAUGCCUG 1126 UUCUA UGC 172 ACAGGCAUCAAGUU 1127 AGUAGAACUUGAUGCC1128 CUACU UGU 173 CAGGCAUCAAGUUC 1129 GAGUAGAACUUGAUGC 1130 UACUC CUG174 AGGCAUCAAGUUCU 1131 GGAGUAGAACUUGAUG 1132 ACUCC CCU 175GGCAUCAAGUUCUA 1133 UGGAGUAGAACUUGAU 1134 CUCCA GCC 176 GCAUCAAGUUCUAC1135 AUGGAGUAGAACUUGA 1136 UCCAU UGC 177 CAUCAAGUUCUACU 1137AAUGGAGUAGAACUUG 1138 CCAUU AUG 178 AUCAAGUUCUACUC 1139 GAAUGGAGUAGAACUU1140 CAUUC GAU 179 UCAAGUUCUACUCC 1141 UGAAUGGAGUAGAACU 1142 AUUCA UGA180 CAAGUUCUACUCCA 1143 CUGAAUGGAGUAGAAC 1144 UUCAG UUG 181AAGUUCUACUCCAU 1145 GCUGAAUGGAGUAGAA 1146 UCAGC CUU 182 AGUUCUACUCCAUU1147 UGCUGAAUGGAGUAGA 1148 CAGCA ACU 183 GUUCUACUCCAUUC 1149CUGCUGAAUGGAGUAG 1150 AGCAG AAC 184 GUGUCAUCUCAGAC 1151 AGGUUGUCUGAGAUGA1152 AACCU CAC 185 CAUCUCAGACAACC 1153 CAGCAGGUUGUCUGAG 1154 UGCUG AUG186 UCAGACAACCUGCU 1155 UCACCAGCAGGUUGUC 1156 GGUGA UGA 187CGGGGACCUGUUAC 1157 UGUCUGUAACAGGUCC 1158 AGACA CCG 188 GACAACGCUGCCAU1159 AGACAAUGGCAGCGUU 1160 UGUCU GUC 189 GCUGCCUCCUGACU 1161AUUACAGUCAGGAGGC 1162 GUAAU AGC 190 CUGCCUCCUGACUG 1163 UAUUACAGUCAGGAGG1164 UAAUA CAG 191 UAAUAUUAAACUU 1165 UUAAAAAAGUUUAAUA 1166 UUUUAA UUA192 AAUAUUAAACUUU 1167 UUUAAAAAAGUUUAAU 1168 UUUAAA AUU

1. A RNAi oligonucleotide for modulating sterol regulatoryelement-binding protein (SREBP) cleavage-activating protein (SCAP)activity, the oligonucleotide comprising a sense strand and an antisensestrand, wherein the sense strand and the antisense strand form a duplexregion, wherein the antisense strand comprises a region ofcomplementarity to a SCAP mRNA target sequence of any one of SEQ ID NOs:777 to 783, and wherein the region of complementarity is at least 15contiguous nucleotides in length.
 2. The RNAi oligonucleotide of claim1, wherein the sense strand is 15 to 50 nucleotides in length. 3.(canceled)
 4. The RNAi oligonucleotide of claim 1, wherein the antisensestrand is 15 to 30 nucleotides in length, optionally wherein theantisense strand is 22 nucleotides in length, and where in the antisensestrand and the sense strand form a duplex region of at least 19nucleotides in length, optionally at least 20 nucleotides in length.5-6. (canceled)
 7. The RNAi oligonucleotide of claim 1, wherein the 3′end of the sense strand comprises a stem-loop set forth as S1-L-S2,wherein S1 is complementary to S2, and wherein L forms a loop between S1and S2 of 3 to 5 nucleotides in length. 8-14. (canceled)
 15. The RNAioligonucleotide of claim 1, wherein the sense strand is 36 nucleotidesin length and the antisense strand is 22 nucleotides in length, whereinthe sense strand and the antisense strand form a duplex region of atleast 19 nucleotides in length, optionally 20 nucleotides in length,wherein the 3′ end of the sense strand comprises a stem-loop set forthas S1-L-S2, wherein S1 is complementary to S2, wherein L forms a loopbetween S1 and S2 of 3 to 5 nucleotides in length, and wherein theregion of complementarity is 19 contiguous nucleotides in length,optionally 20 nucleotides in length.
 16. The RNAi oligonucleotide ofclaim 15, wherein L is a triloop or a tetraloop, optionally wherein thetetraloop comprises a sequence of 5′-GAAA-3′. 17-18. (canceled)
 19. TheRNAi oligonucleotide of claim 15, wherein S1 and S2 are 1-10 nucleotidesin length and have the same length, optionally wherein the stem-loopcomprises the sequence 5′-GCAGCCGAAAGGCUGC-3′ (SEQ ID NO: 784). 20-22.(canceled)
 23. The RNAi oligonucleotide of claim 1, wherein theantisense strand comprises a 3′ overhang sequence of 1 or morenucleotides in length, optionally wherein the 3′ overhang sequence is 2nucleotides in length, and optionally wherein the 3′ overhang sequenceis GG.
 24. (canceled)
 25. The RNAi oligonucleotide of claim 1 comprisingat least 1 modified nucleotide.
 26. (canceled)
 27. The RNAioligonucleotide of claim 25, wherein the modified nucleotide comprises a2′-modification, optionally wherein the 2′-modification is amodification selected from the group consisting of 2′-aminoethyl,2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl, and2′-deoxy-2′-fluoro-β-d-arabinonucleic acid.
 28. (canceled)
 29. The RNAioligonucleotide of claim 1, wherein all nucleotides comprising the RNAioligonucleotide are modified, and optionally wherein the modification isa 2′-modification selected from the group consisting of 2′-fluoro and2′-O-methyl.
 30. The RNAi oligonucleotide of claim 29, wherein: (i) oneor more nucleotides at positions 8, 9, 10, or 11 of the sense strand aremodified with 2′-fluoro; (ii) one or more nucleotides at positions 2, 3,4, 5, 7, 10, or 14 of the antisense strand are modified with 2′-fluoro;(iii) one or more nucleotides at positions 1, 2, 3, 4, 5, 6, 7, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 31, 32, 33, 34,35, or 36 of the sense strand are modified with 2′-O-methyl; or (iv) oneor more nucleotides at positions 1, 6, 8, 9, 11, 12, 13, 15, 16, 17, 18,19, 20, 21, or 22 of the antisense strand are modified with 2′-O-methyl.31-33. (canceled)
 34. The RNAi oligonucleotide of claim 1 comprising atleast one modified internucleotide linkage, optionally wherein the atleast one modified internucleotide linkage is a phosphorothioatelinkage.
 35. (canceled)
 36. The RNAi oligonucleotide of claim 34,wherein the internucleotide linkage of nucleotides at positions 1 and 2of the sense strand are modified with the phosphorothioate linkage. 37.The RNAi oligonucleotide of claim 34, wherein the internucleotidelinkage of one or more nucleotides at positions 1 and 2, 2 and 3, 3 and4, 20 and 21, or 21 and 22 of the antisense strand are modified with thephosphorothioate linkage.
 38. (canceled)
 39. The RNAi oligonucleotide ofclaim 1, wherein the 4′-carbon of the sugar of the 5′-nucleotide of theantisense strand comprises a phosphate analog, optionally wherein thephosphate analog is oxymethylphosphonate, vinyl phosphonate ormalonylphosphonate, and further optionally wherein the phosphate analogis a 4′-phosphate analog comprising 5′-methoxyphosphonate-4′-oxy. 40.(canceled)
 41. The RNAi oligonucleotide of claim 1, wherein at least onenucleotide of the oligonucleotide is conjugated to one or more targetingligands.
 42. (canceled)
 43. The RNAi oligonucleotide of claim 41,wherein each targeting ligand comprises a N-acetylgalactosamine (GalNAc)moiety, optionally wherein the GalNAc moiety is a monovalent GalNAcmoiety, a bivalent GalNAc moiety, a trivalent GalNAc moiety, or atetravalent GalNAc moiety.
 44. (canceled)
 45. The RNAi oligonucleotideof claim 1 wherein up to 4 nucleotides of L of the stem-loop are eachconjugated to a monovalent GalNAc moiety.
 46. The RNAi oligonucleotideof claim 1, wherein the sense strand comprises a nucleotide sequence ofany one of the odd numbers of SEQ ID NOs: 9 to
 392. 47. The RNAioligonucleotide of claim 1, wherein the antisense strand comprises anucleotide sequence of any one of the even numbers of SEQ ID NOs:9 to392.
 48. The RNAi oligonucleotide of claim 1, wherein the sense strandand the antisense strands comprise nucleotide sequences selected fromthe group consisting of: (a) SEQ ID NOs: 139 and 140, respectively; (b)SEQ ID NOs: 147 and 148, respectively; (c) SEQ ID NOs: 221 and 222,respectively; (d) SEQ ID NOs: 273 and 274, respectively; (e) SEQ ID NOs:321 and 322, respectively; (f) SEQ ID NOs: 333 and 334, respectively;and (g) SEQ ID NOs: 361 and 362 respectively. 49-55. (canceled)
 56. TheRNAi oligonucleotide of claim 48, wherein the sense strand and theantisense strands comprise nucleotide sequences selected from the groupconsisting of: (a′) SEQ ID NOs: 523 and 524, respectively; (b′) SEQ IDNOs: 531 and 532, respectively; (c′) SEQ ID NOs: 605 and 606,respectively; (d′) SEQ ID NOs: 657 and 658, respectively; (e′) SEQ IDNOs: 705 and 706, respectively; (f′) SEQ ID NOs: 717 and 718,respectively; and (g′) SEQ ID NOs: 745 and 746 respectively. 57-91.(canceled)
 92. A pharmaceutical composition comprising: the RNAioligonucleotide of claim 1, or a pharmaceutically acceptable saltthereof; and a pharmaceutically acceptable carrier, delivery agent orexcipient.
 93. (canceled)
 94. A method of treating an individual havinga disease, disorder, or condition associated with sterol regulatoryelement-binding protein (SREBP) cleavage-activating protein (SCAP)activity, the method comprising the step of: administering to theindividual a therapeutically effective amount of the RNAioligonucleotide of claim 1, thereby treating the individual.
 95. Amethod of reducing sterol regulatory element-binding protein (SREBP)cleavage-activating protein (SCAP) activity in a cell, a population ofcells or an individual, the method comprising the step of: contactingthe cell or the population of cells with the RNAi oligonucleotide ofclaim 1; or administering to the individual the RNAi oligonucleotide ofclaim
 1. 96-116. (canceled)